Index of Analyses December 2016 Imprint

We reserve the right for errors and alterations. Our laboratory is part of the synlab group. © 2nd edition 2016/2017 By SYNLAB Medizinisches Versorgungszentrum Humane Genetik Medical Practice and Laboratory for Human genetics

2 Medical Director Dr. med. Dr. rer. nat. Claudia Nevinny-Stickel Consultant Human geneticist

Postal Address Lindwurmstrasse 23 D-80337 Munich Germany

Telephone and Fax Reception +49 (0)89. 54 86 29 -0 Invoicing -0 Fax -243 Molecular Genetics -554 Cytogenetics -559

Office hours Monday – Friday 8.30 – 18.00 [email protected] www.humane-genetik.de 3 Table of contents

Preanalytics...... 06 Molecular genetic analyses...... 09 Cardiac diseases...... 08 Complex syndromes...... 11 Connective Tissue Disorders...... 20 Endocrinology...... 22 Eye diseases...... 24 Fertility disorders...... 25 Gastrointestinal diseases...... 26 Hematology...... 27 Hemophilia...... 28 Hereditary cancer syndromes...... 30 Immune disorders...... 36 Intersexuality...... 37 Kidney diseases...... 37 Liver diseases...... 39 Lung diseases...... 42 Metabolic diseases...... 42 Mitochondrial diseases...... 52 Neurodegenerative diseases...... 54 Neuromuscular diseases /Neuropathies...... 57 Nutrigenetics...... 62 Pancreatic diseases...... 63 Periodic fever...... 63 Pharmacogenetics...... 65 Short stature...... 67 Thrombophilia / Atherosclerosis...... 68 Uniparental disomies...... 73 Kinship Analyses...... 73 Cytogenetics and molecular cytogenetics...... 74 Prenatal chromosome diagnostics...... 74 Postnatal chromosome diagnostics...... 76 Molecular cytogenetics...... 78 Chromosomal microarray diagnostics...... 81 Quality assurance...... 82 Index...... 84

4 Preanalytics

Testing Material For genetic testing nuclei-containing cells of the patient are required, which are either cultivated or subjected to DNA extraction. Cells can be harvested from peripheral blood, buccal swabs, amniotic fluid, chorionic villi (CVS), or tissue samples. In case of blood collection, no special preparation of the patient, e.g. fasting, is required. The sample may be collected at any time of the day. The blood collection must be performed under sterile conditions. The tubes should always be filled up to the measure line to guarantee an optimal ratio between blood and anticoagulants. Please invert the tubes carefully after blood collection to allow adequate mixing of blood and anticoagulants. Blood samples should not be older than one week. Please make sure that the samples are sent to our laboratory immediately at ambient temperature, and avoid extreme temperatures during the transport.

5 Preanalytics

Cytogenetic and Molecular Cytogenetic Analyses 5 ml sterile heparin blood (infants and young children < 5 ml) 10-15 ml amniotic fluid 10-20 mg chorionic villi (CVS) Aborted fetal tissue with chorionic villi (CVS) Skin biopsy Buccal swab

Chromosomal Microarray Analyses: 3-5 ml EDTA-blood, or 2 µg high quality DNA. In case of a conspicuous finding, 3-5 ml heparin blood from the patient is needed for validation of the result by FISH-analysis. In addition, EDTA-blood or 2 µg high quality DNA, and heparin blood of the parents may be necessary.

Molecular Genetic Analyses 5 ml EDTA-blood (infants and young children < 3 ml) Amniotic fluid Chorionic villi (CVS) Aborted fetal tissue Tissue Skin biopsy Buccal swabs In general, EDTA-blood is the most suitable material for molecular genetic analyses. Please inquire if other genetic material is suitable for the requested analysis if blood collection is not possible.

Kinship Analyses 3 buccal swabs or 3-5 ml EDTA-blood

6 Preanalytics

Sample Identification and Required Forms Sample tubes and the corresponding request forms must be clearly labelled with the patient’s name and date of birth for correct identification. Our request forms are available for download at www.humane-genetik.de/en/forms/. Please state the indication for the requested analysis. A short anamnesis as well as family history will significantly support our experts in performing the optimal analysis and for assessing the findings . According to German law, the informed consent form must be signed either by the patient (or his/her legal representative) or by the referring physician. This form is mandatory for every genetic analysis and must be sent together with the sample and the request forms. Please note that w require prepayment. Prices of our analyses are available on request [email protected]. If you are part of the Synlab group, samples may be dispatched to Synlab MVZ in Leinfelden, Germany, as the primary hub for all incoming samples originating in foreign countries. Samples will then be forwarded to MVZ Humane Genetik Munich accordingly. The spectrum of our genetic analyses is continually expanding. An updated version of the genetic analyses we currently offer can be accessed on our website www.humane-genetik.de/en/. Genetic analyses not offered by our laboratory can be performed in co-operation with other accredited laboratories. Please inquire.

7 Molecular genetic analyses

Cardiac diseases

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) OMIM: 609040 Gene: PKP2, locus 12p11.21 Inheritance: autosomal dominant Indication: right- or biventricular dilation, arrhythmia, syncope, family history of sudden cardiac death Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of PKP2 (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of PKP2 (approx. 2 wks)

Brugada syndrome, BrS1 OMIM: 601144 Gene: SCN5A, locus 3p21-23 Inheritance: usually autosomal dominant, variable penetrance Indication: ECG anomalies (T-wave alternans, QT-segment elevation), syncope, absence of structural cardiac disease, family history of sudden cardiac death Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of SCN5A (approx. 3 wks) 2nd tier: deletion/duplication analysis (MLPA) of SCN5A (approx. 2 wks)

8 Molecular genetic analyses

Cardiomyopathy (hypertrophic/dilated) OMIM: 115197, 613426, 192600, 601494, 115195, 11880, 613690, 115200 Genes: MYBPC3, MYH7, TNNT2, TNNI3 and LMNA, loci 11p11.2, 14q11.2, 1q32.1, 19q13.42, 1q22 Inheritance: autosomal dominant Indication: right- or biventricular dilation, arrhythmia, syncope, family history of sudden cardiac death Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of MYBPC3 (approx. 4 wks) 2nd tier: sequencing analysis of MYH7 (approx. 4 wks) 3rd tier: sequencing analysis of TNNT2 (approx. 3 wks) 4th tier: sequencing analysis of TNNI3 (approx. 2 wks) 5th tier: sequencing analysis of LMNA (approx. 2 wks) 6th tier: deletion/duplication analysis (MLPA) of MYBPC3 (approx. 2 wks) 7th tier: deletion/duplication analysis (MLPA) of MYH7 (approx. 2 wks) 8th tier: deletion/duplication analysis (MLPA) of TNNT2 (approx. 2 wks)

Catecholaminergic polymorphic ventricular tachycardia (CPVT) OMIM: 604772 Gene: RYR2, locus 1q43 Inheritance: autosomal dominant Indication: polymorphic ventricular tachycardia induced by physical activity, stress, no structural cardiac abnormalities, recurrent syncope Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of select regions of RYR2 (approx. 3 wks) 2nd tier: sequencing analysis of remaining regions of RYR2 (approx. 3 wks) 3rd tier: deletion/duplication analysis (MLPA) of exon 3 of RYR2 (approx. 2 wks)

9 Molecular genetic analyses

Long QT syndrome (LQT1, LQT2, LQT3, LQT5, LQT6) OMIM: 192500, 613688, 603830, 613695, 613693 Genes: KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, loci 11p15.5, 7q35- 36, 3p21-23, 21q22.1-22.2 Inheritance: usually autosomal dominant, variable penetrance Indication: ECG anomalies (prolongation of the QTc-interval, T-wave abnormalities), syncope, absence of structural cardiac disease, family history of sudden cardiac death Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of KCNQ1 (approx. 2 wks) 2nd tier: sequencing analysis of KCNH2 (approx. 2 wks) 3rd tier: sequencing analysis of SCN5A (approx. 3 wks) 4th tier: sequencing analysis of KCNE1 (approx. 2 wk) 5th tier: sequencing analysis of KCNE2 (approx. 2 wk) 6th tier: deletion/duplication analysis (MLPA) of KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 (approx. 2 wks)

Short QT syndrome (SQT1, SQT2) OMIM: 609620, 609621 Genes: KCNH2, KCNQ1, loci 7q35-36, 11p15.5 Inheritance: usually autosomal dominant, variable penetrance Indication: short QTc-interval in ECG, ventricular fibrillation, syncope, absence of structural cardiac disease, family history of sudden cardiac death Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of KCNH2 (approx. 2 wks) and KCNQ1 (approx. 2 wks)

10 Molecular genetic analyses

Complex syndromes

Aarskog syndrome (Faciogenital Dysplasia) OMIM: 305400 Gene: FGD1, locus Xp11.21 Inheritance: X-linked recessive Indication: suspected faciogenital dysplasia, short stature, hypertelorism, shawl scrotum, and brachydactyly Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of FGD1 (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of FGD1 (approx. 2 wks)

Angelman syndrome (AS) OMIM: 105830 Gene: SNRPN gene locus; UBE3A, Locus 15q11-13 Inheritance: sporadic/autosomal dominant Indication: severe mental retardation with profound speech impairment, gait ataxia and/or tremulousness of the limbs, unique behaviour with an inappropriate happy demeanour, microcephaly and seizures, hypotonia Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: methylation sensitive deletion/duplication analysis (MS-MLPA) SNRPN-gene locus (approx. 3 wks) 2nd tier (for inconspicuous result from MS-MLPA): sequencing analysis of UBE3A (approx. 2 wks) 3rd tier (for conspicuous result from MS-MLPA): uniparental disomy 15 (UPD15) analysis, parents’ sample required (approx. 2 wks)

11 Molecular genetic analyses

Beckwith-Wiedemann syndrome (BWS) OMIM: 130650 Gene: H19 / KCNQ1OT1 gene locus; locus 11p15.5 Inheritance: sporadic/autosomal dominant Indication: macrosomia (large body size), macroglossia, visceromegaly, embryonal tumors (e.g. Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma), omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, renal abnormalities (e.g. medullary dysplasia, nephrocalcinosis, medullary sponge kidney, and nephromegaly) Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: methylation sensitive deletion/duplication analysis (MS-MLPA) (approx. 3 wks) 2nd tier (for conspicuous result from MS-MLPA): uniparental disomy 11 (UPD11) analysis, parents’ sample required (approx. 2 wks)

Costello syndrome OMIM: 218040 Gene: HRAS, locus 11p15.5 Inheritance: autosomal dominant Indication: short stature, characteristic coarse facies, redundant skin of the neck, palms, soles, and fingers, severe feeding difficulty, failure to thrive, cardiac anomalies and developmental disability Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of select regions of HRAS (approx. 2 wks)

12 Molecular genetic analyses

DiGeorge syndrome OMIM: 188400 Loci: 22q11.2, 10p14 (DGS2) Inheritance: autosomal dominant Indication: congenital heart disease, particularly conotruncal malformations (tetralogy of Fallot, interrupted aortic arch, ventricular septal defect, and truncus arteriosus); palatal abnormalities, particularly velopharyngeal incompetence (VPI), submucosal cleft palate, and cleft palate, hypocalcemia Material: 3-5 ml EDTA blood Methods/TAT: deletion/duplication analysis (MLPA) of DiGeorge region (approx. 2 wks)

Fragile X syndrome (Martin-Bell syndrome, FraX-A) OMIM: 309550 Gene: FMR1, locus Xq27.3 Inheritance: X-linked Indication: mental retardation particularly in males, incidence 1:1250, determination of carrier status in members of risk families, clinical suspicion of premature ovarian insufficiency (POI) or FraX-associated tremor/ataxia syndrome (FXTAS) Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: fragment length analysis (approx. 2 wks) and Southern Blot analysis for the determination of the CGG- repeat length in the promotor region of FMR1 (approx. 3 wks), prenatal analysis: approx. 1 week 2nd tier: sequencing analysis of FMR1 (approx. 3 wks) 3rd tier: methylation sensitive deletion/duplication analysis (MS-MLPA) FMR1 locus (approx. 3 wks)

13 Molecular genetic analyses

Fragile X syndrome (FraX-E) OMIM: 309548 Gene: AFF2, Locus Xq28 Inheritance: X-linked Indication: mental retardation particularly in males, analysis of the carrier status in families with positive family history for Fragile X-syndrome Material: 3-5 ml EDTA blood Methods/TAT: fragment length analysis (approx. 2 wks) and Southern Blot analysis for the determination of the GCC-repeat length in the AFF2 gene (approx. 3 wks), prenatal analysis: approx. 1 week

Hypoparathyroidism, Deafness, and Renal Disease (HDR) OMIM: 146255 Gene: GATA3, locus 10p15 Inheritance: autosomal dominant Indication: hypocalcemia, tetany, hearing loss (usually bilateral ranging from mild to profound impairment), renal disease manifestations: nephrotic syndrome, cystic kidney, renal dysplasia, hypoplasia or aplasia, pelvicalyceal deformity, vesicoureteral reflux, chronic renal failure, hematuria, proteinuria and renal scarring Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of GATA3 (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of GATA3 (approx. 2 wks)

14 Molecular genetic analyses

Kallmann syndrome OMIM: 308700, 147950, 610628, 244200 Genes: KAL1, FGFR1, PROK2, PROKR2, loci Xp22.3, 8p11.2-p11.1, 3p13, 20p12.3 Inheritance: X-linked recessive (KAL1), autosomal dominant (FGFR1, PROK2, PROKR2) Indication: idiopathic or isolated hypogonadotropic hypogonadism (IHH) and anosmia or hyposmia Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of KAL1 (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of KAL1 (approx. 2 wks) 3rd tier: sequencing analysis of FGFR1 (approx. 3 wks) 4th tier: sequencing analysis of PROK2 (approx. 2 wks) 5th tier: sequencing analysis of PROKR2 (approx. 2 wks) 6th tier: deletion/duplication analysis (MLPA) of FGFR1, PROK2, PROKR2 (approx. 2 wks)

LEOPARD syndrome OMIM: 151100 Gene: PTPN11, locus 12q24.1 Inheritance: autosomal dominant Indication: LEOPARD = lentiginosis, ECG-abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retarded growth, deafness Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of select regions of PTPN11 (approx. 2 wks) 2nd tier: sequencing analysis of remaining regions of PTPN11 (approx. 2 wks) 3rd tier: sequencing analysis of RAF1 (approx. 3 wks) 4th tier: sequencing analysis of BRAF (approx. 3 wks)

15 Molecular genetic analyses

Noonan syndrome OMIM: 163950, 610733, 611553, 609942, 613706 Genes: PTPN11 (type 1), SOS1 (type 4), RAF1 (type 5), KRAS (type 3), BRAF (type 7), loci 12q24.1, 2p22-p21, 3p25.2, 12p12.1, 7q34 Inheritance: autosomal dominant Indication: congenital heart defect, pulmonary stenosis, cardiac hypertrophy, short stature, triangular shaped face, hypertelorism, cryptorchidism, in some cases slight mental retardation Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of select regions of PTPN11 (approx. 2 wks) 2nd tier: sequencing analysis SOS1 (approx. 3 wks) 3rd tier: sequencing analysis of remaining regions of PTPN11 (approx. 2 wks) 3rd tier: sequencing analysis of RAF1 (approx. 3 wks) 4th tier: sequencing analysis of KRAS (approx. 2 wks) 5th tier: sequencing analysis of BRAF (approx. 3 wks)

Osler-Rendu-Weber disease OMIM: 187300, 600376 Genes: ENG, ACVRL1, loc 9q34.11, 12q13.13 Inheritance: autosomal dominant Indication: hereditary hemorrhagic telangiectasia, arteriovenous malformations, nosebleeding, gastrointestinal bleeding Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis ENG (approx. 2 wks) 2nd tier: sequencing analysis ACVRL1 (approx. 2 wks) 3rd tier: deletion/duplication analysis (MLPA) of ENG and ACVRL1 (approx. 2 wks)

16 Molecular genetic analyses

Prader-Willi syndrome (PWS) OMIM: 176270 Gene: SNRPN, locus 15q11-13, UPD 15 Inheritance: sporadic/autosomal dominant Indication: severe hypotonia and feeding difficulties in early infancy, followed in later infancy or early childhood by excessive eating and gradual development of morbid obesity, delayed motor milestones and language development, cognitive impairment, hypogonadism and genital hypoplasia Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: methylation sensitive deletion/duplication analysis (MLPA) SNRPN locus (approx. 3 wks) 2nd tier (for conspicuous result from MS-MLPA): uniparental disomy 15 (UPD15) analysis, parents’ sample required (approx. 2 wks)

Proteus syndrome OMIM: 176920 Gene: AKT1, locus 14q32.3 Inheritance: de novo, mosaicism for a somatic activating mutation in the AKT1 gene Indication: asymmetric and disproportionate overgrowth of body parts, connective tissue nevi, epidermal nevi, dysregulated adipose tissue, vascular malformations, cerebriform connective tissue nevus Material: skin punch or tissue from affected region Methods/TAT: Sequencing analysis of select regions of AKT1 (approx. 2 wks)

17 Molecular genetic analyses

Rett syndrome OMIM: 312750 Gene: MECP2, locus Xq28 Inheritance: X-linked dominant Indication: mental retardation particularly in females, normal psychomotor development during the first six to 18 months of life, followed by a short period of developmental stagnation, then rapid regression in language and motor skills, autism, repetitive, stereotypic hand movements Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis MECP2 (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of MECP2 (approx. 2 wks)

Silver-Russell syndrome (SRS) OMIM: 180860 Gene: H19/IGF2 gene locus; locus 11p15.5 Inheritance: sporadic/autosomal dominant Indication: intrauterine growth retardation accompanied by postnatal growth deficiency, proportionately short stature, normal head circumference, fifth-finger clinodactyly, typical facial features and limb-length asymmetry that may result from hemihypotrophy Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: methylation sensitive deletion/duplication analysis (MS-MLPA) H19/IGF2 gene locus (approx. 3 wks) 2nd tier: uniparental disomy 7(UPD7 analysis) (parents’ sample required) (approx. 2 wks)

18 Molecular genetic analyses

Sotos syndrome OMIM: 117550 Gene: NSD1, locus 5q35 Inheritance: autosomal dominant Indication: typical facial appearance, macrocephaly, overgrowth (height and head circumference ≥2 SD above the mean), learning disability ranging from mild to severe Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis NSD1 (approx. 3 wks) 2nd tier: deletion/duplication analysis (MLPA) of NSD1 (approx. 2 wks)

Thrombocytopenia-absent radius syndrome (TAR) OMIM: 274000 Gene: RBM8A, locus 5q35 Inheritance: autosomal recessive Indication: reduced number of platelets, thrombocytopenia, absence of the radius but preservation of the thumb Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of select regions of RBM8A (approx. 2 wks) and deletion/duplication analysis (MLPA) of RBM8A (approx. 2 wks)

Williams-Beuren syndrome OMIM: 194050, 609757 Gene: WBSCR region, locus 7q11.2 Inheritance: autosomal dominant Indication: cardiovascular disease, supravalvular aortic stenosis (SVAS), elastin arteriopathy, peripheral pulmonary stenosis, hypertension, distinctive facies, mental retardation (usually mild), a specific cognitive profile, unique personality characteristics, growth abnormalities and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism and early puberty) Material: 3-5 ml EDTA blood Methods/TAT: deletion/duplication analysis (MLPA) of WBSCR region (approx. 2 wks)

19 Molecular genetic analyses

Connective Tissue Disorders

Ehlers-Danlos syndrome types I+II (classical type) OMIM: 130000, 130010 Gene: COL5A1, COL5A2, loci 9q34, 2q31 Inheritance: autosomal dominant Indication: joint hypermobility, hyperextensible skin, atrophic and “cigarette paper” scars Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of COL5A1 (approx. 3 wks) 2nd tier: sequencing analysis of COL5A2 (approx. 3 wks) 3rd tier: deletion/duplication analysis (MLPA) of COL5A1 (approx. 2 wks)

Ehlers-Danlos syndrome type IV (vascular type) OMIM: 130050 Gene: COL3A1, locus 2q31 Inheritance: autosomal dominant Indication: skin hyperextensibility, atrophic scarring, easy bruising, thin and translucent skin, joint hypermobility, rupture of inner organs and arteries, facial appearance: hollow cheeks, prominent staring eyes, pinched nose, lobeless ears Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of COL3A1 (approx. 4 wks) 2nd tier: deletion/duplication analysis (MLPA) of COL3A1 (approx. 2 wks)

Ehlers-Danlos syndrome type VI (Kyphoscoliosis) OMIM: 225400 Gene: PLOD1, locus 1p36 Inheritance: autosomal recessive Indication: generalized joint laxity, progressive scoliosis, scleral fragility and globe rupture, muscle hypotonia at birth, tissue fragility Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: deletion/duplication analysis (MLPA) of PLOD1 (approx. 2 wks) 2nd tier: sequencing analysis of PLOD1 (approx. 3 wks)

20 Molecular genetic analyses

Ehlers-Danlos syndrome types VIIA+B (Arthrochalasia) OMIM: 130060 Genes: COL1A1, COL1A2, loci 17q32.32, 7q22.1 Inheritance: autosomal dominant Indication: severe generalized joint hypermobility, recurrent subluxations, congenital hip dislocation, skin hyperextensibility, atrophic scars Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of select regions of COL1A1 and COL1A2 (approx. 3 wks) 2nd tier: deletion/duplication analysis (MLPA) of COL1A1 and COL1A2 (approx. 2 wks)

Loeys-Dietz syndrome OMIM: 609192, 610168 Genes: TGFBR1, TGFBR2, loci 9q22, 3p22 Inheritance: autosomal dominant Indication: typical facial dysmorphic features (hypertelorism, cleft palate/bifid uvula, craniosynostosis), aggressive arterial/ aortic aneurysm, arterial tortuosity, Marfan syndrome like appearance Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of TGFBR1 (approx. 2 wks) 2nd tier: sequencing analysis of TGFBR2 (approx. 2 wks) 3rd tier: deletion/duplication analysis (MLPA) of TGFBR1 and TGFBR2 (approx. 2 wks)

Marfan syndrome OMIM: 154700 Gene: FBN1, locus 15q21.1 Inheritance: autosomal dominant Indication: connective tissue weakness, bone overgrowth with disproportionately long extremities and joint laxity, aortic root dilatation, aortic aneurysm, myopia, ectopia lentis Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of FBN1 (approx. 4 wks) 2nd tier: deletion/duplication analysis (MLPA) of FBN1 (approx. 2 wks)

21 Molecular genetic analyses

Osteogenesis Imperfecta OMIM: 166200, 166210 Genes: COL1A1, COL1A2, loci 17q32.32, 7q22.1 Inheritance: autosomal dominant Indication: increased bone fragility with variable severity, blue sclera, dentinogenesis imperfecta, hearing impairment Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of COL1A1 (approx. 3 wks) 1st tier: sequencing analysis of COL1A2 (approx. 3 wks) 2nd tier: deletion/duplication analysis (MLPA) of COL1A1 and COL1A2 (approx. 2 wks)

Endocrinology

Congenital adrenal hyperplasia (CAH) 21-Hydroxylase deficiency OMIM: 201910 Gene: CYP21A2, locus 6p21.3 Inheritance: autosomal recessive Indication: Congenital adrenal hyperplasia, salt wasting, precocious puberty or adrenarche, virilization, hirsutism Material: 3-5 ml EDTA blood Methods/TAT: deletion/duplication analysis (MLPA) (approx. 2 wks) and Sequencing analysis of CYP21A2 (approx. 2 wks), prenatal analysis altogether approx. 1 week

Steroid 11-beta-Hydroxylase deficiency OMIM: 202010 Gene: CYP11B1, locus 8q24.3 Inheritance: autosomal recessive Indication: low renin hypertension, hypokalemia, hyperandrogenemia, virilization, genital ambiguity in females Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of CYP11B1 (approx. 2 wks)

22 Molecular genetic analyses

17-alpha-Hydroxylase deficiency OMIM: 202110 Gene: CYP17A1, locus 10q24.32 Inheritance: autosomal recessive Indication: impaired cortisol synthesis, low renin hypertension, hypokalemia, metabolic alkalosis Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of CYP17A1 (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of CYP17A1 (approx. 2 wks)

3-beta-Hydroxysteroid Dehydrogenase 2 deficiency OMIM: 201810 Gene: HSD3B2, locus 1p12 Inheritance: autosomal recessive Indication: severe salt wasting, genital ambiguity in males and females Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of HSD3B2 (approx. 2 wks)

Hyperinsulinism > please refer to “Metabolic diseases”

Hyperproinsulinemia > please refer to “Metabolic diseases”

Kallmann syndrome > please refer to “Complex syndromes”

Maturity-Onset Diabetes of the Young (MODY) > please refer to “Metabolic diseases”

Neonatal Diabetes (Permanent/transient) > please refer to “Metabolic diseases”

23 Molecular genetic analyses

Obesity (early onset) OMIM: 601665, 602025, 609734, 614963, 614962 Genes: MC4R, MC3R, POMC, LEPR, LEP, loci 18q21.32, 20q13.2, 2p23.3, 1p31.3, 7q32.1 Inheritance: autosomal dominant (MC4R, MC3R), autosomal recessive (POMC, LEPR, LEP) Indication: severe and early onset obesity, increased lean mass, increased linear growth, hyperphagia, and severe hyperinsulinemia Material: 3-5 ml EDTA blood Methods/TAT: 1st tier Sequencing analysis of MC4R (approx. 2 wks) 2nd tier Sequencing analysis of LEPR (approx. 2 wks) 3rd tier Sequencing analysis of MC3R, POMC, LEP (approx. 2 wks) 4th tier: deletion/duplication analysis (MLPA) of MC4R, MC3R, POMC, LEPR, LEP (approx. 2 wks)

Eye diseases

Leber’s hereditary optic neuropathy (LHON) OMIM: 535000 Genes: MTND1, MTND4, MTND6, mitochondrial genome Inheritance: mitochondrial Indication: bilateral, painless, subacute visual failure that develops during young adult life, unilateral or bilateral optic neuropathy, centrocecal scotoma Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of the common mutations m.11778G>A, m.3460G>A, m.14484T>C (approx. 2 wks)

24 Molecular genetic analyses

Optic Atrophy 1 (OPA1) OMIM: 165500 Gene: OPA1, locus 3q28-q29 Inheritance: autosomal dominant Indication: bilateral neuropathy of the optic nerve, scotoma Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of OPA1 (approx. 3 wks) 2nd tier: deletion/duplication analysis (MLPA) of OPA1 (approx. 2 wks)

Fertility disorders

Habitual miscarriages Factor V, Leiden mutation OMIM: 227400 Gene: F5, Locus 1q23 Inheritance: polygenic/multifactorial Indication: thrombosis, habitual miscarriages Material: 3-5 ml EDTA blood Methods/TAT: Real-time-PCR (LightCycler technique), genotyping of the Leiden mutation c.1601G>A p.(Arg534Gln) in the F5 gene (approx. 1 wk)

Mannose binding lectin (MBL) OMIM: 614372 Gene: MBL2, locus 10q21.1 Inheritance: polygenic/multifactorial Indication: recurrent preterm births due to chorioamnionitis Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of MBL2, detection of the haplotypes HYPA, HYPD, LYPA, LYQA, LXPA, LYPB, LYQC (approx. 2 wks)

25 Molecular genetic analyses

Male infertility Azoospermia factor (AZF) OMIM: 415000 Gene: AZF-locus Yq11 Inheritance: Y-chromosomal Indication: infertility due to non-obstructive azoospermia, oligozoospermia, cryptozoospermia Material: 3-5 ml EDTA blood Methods/TAT: PCR; detection of microdeletions in the AZF region (approx. 2 wks)

Congenital bilateral aplasia of the vas deferens (CBAVD) OMIM: 277180 Gene: CFTR, locus 7q31.3 Inheritance: autosomal recessive Indication: infertility due to obstructive azoospermia Material: 3-5 ml EDTA blood Methods/TAT: panel for 50 common mutations (approx. 2 wks) sequencing analysis of CFTR, deletion/duplication analysis (MLPA) of CFTR (approx. 4 wks)

Gastrointestinal diseases Celiac disease OMIM: 146880, 604305 Gene: Major Histocompatibility Complex DQA1, DQB1, locus 6p21.3 Inheritance: polygenic/multifactorial Indication: gluten-sensitive enteropathy, malabsorption resulting from inflammatory injury to the mucosa Material: 3-5 ml EDTA blood Methods/TAT: sequence specific PCR (SSP) (approx. 2 wks)

26 Molecular genetic analyses

Inflammatory bowel disease (Crohn disease) OMIM: 266600 Gene: NOD2, locus 16q12.1 Inheritance: polygenic/multifactorial Indication: relapsing intestinal inflammation Material: 3-5 ml EDTA blood Methods/TAT: sequencing analysis of NOD2, detection of the mutations p.(Arg702Trp), p.(Gly908Arg), p.(Leu1007Profs*2) (approx. 2 wks)

Hematology

α-Thalassemia OMIM: 141800 Genes: HBA1, HBA2, locus 16pter-p13.3 Inheritance: autosomal, variable phenotype Indication: microcytic hypochromic anemia Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: deletion/duplication analysis (MLPA) of HBA1 and HBA2 (approx. 2 wks) 2nd tier: sequencing analysis of HBA1 and HBA2 (approx. 2 wks)

β–Thalassemia OMIM: 141900 Gene: HBB, locus 11p15.5 Inheritance: autosomal, variable phenotype Indication: microcytic hypochromic anemia, increased amounts of hemoglobin A2 (HbA2) and F (HbF) Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of HBB (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of HBB (approx. 2 wks)

27 Molecular genetic analyses

Glucose-6-Phosphate Dehydrogenase Deficiency OMIM: 305900 Gene: G6PD, locus Xq28 Inheritance: X-chromosomal recessive Indication: anemia (nonspherocytic hemolytic anemia), hemolytic episodes, favism Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of G6PD (approx. 2 wks)

Sickle Cell Anemia OMIM: 603903 Gene: HBB, locus 11p15.5 Inheritance: autosomal recessive Indication: suspected sickle cell anemia Material: 3-5 ml EDTA blood Methods/TAT: Real-time-PCR (LightCycler technique), detection of the mutations HbS (p.(Glu7Val)) and HbC (p.(Glu7Lys)) (approx. 1 wk)

Hemophilia

Hemophilia A OMIM: 306700 Gene: F8, locus Xq28 Inheritance: X-chromosomal recessive Indication: excessive bleeding after injury or surgery, muscle or joint hemorrhage Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: PCR and inverse PCR to detect inversions of introns 1 and 22 (approx. 2 wks) 2nd tier: sequencing analysis of F8 (approx. 3 wks) 3rd tier: deletion/duplication analysis (MLPA) of F8 (approx. 2 wks)

28 Molecular genetic analyses

Hemophilia B OMIM: 306900 Gene: F9, locus Xq27.1 Inheritance: X-chromosomal recessive Indication: excessive bleeding after injury or surgery, muscle or joint hemorrhage Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of F9 (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of F9 (approx. 2 wks)

Von-Willebrand disease OMIM: 193400, 613554, 277480 Gene: VWF, locus 12p13.31 Inheritance: autosomal recessive and autosomal dominant Indication: hemorrhagic diathesis, conspicuous result from biochemical blood clotting analysis Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of VWF (approx. 4 wks) 2nd tier: deletion/duplication analysis (MLPA) of VWF (approx. 2 wks)

29 Molecular genetic analyses

Hereditary cancer syndromes For analyses of hereditary cancer syndromes we kindly request information regarding the personal and family medical history of the patient or counselee. Please find the respective form on our website.

Ataxia teleangiectasia OMIM: 208900 Gene: ATM, locus 11q22.3 Inheritance: autosomal recessive Indication: progressive cerebellar ataxia, oculomotor apraxia, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, frequent infections, leukemia and lymphoma Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of ATM (approx. 4 wks) 2nd tier: deletion/duplication analysis (MLPA) of ATM (approx. 2 wks)

Familial adenomatous polyposis (FAP) OMIM: 611731, 608456 Genes: APC, MUTYH, loci 5;21-;22, 1p34.1 Inheritance: autosomal dominant (APC) and autosomal recessive (MUTYH) Indication: suspected classic or attenuated FAP, flat adenoma syndrome, suspected Gardner syndrome or Turcot syndrome, suspected classic FAP with extracolonic manifestations Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of APC (approx. 3 wks) 2nd tier: deletion/duplication analysis (MLPA) of APC (approx. 2 wks) 3rd tier: sequencing analysis of select regions of MUTYH (approx. 2 wks) 4th tier: sequencing analysis of remaining regions of MUTYH (approx. 2 wks) 5th tier: deletion/duplication analysis (MLPA) of MUTYH (approx. 2 wks)

30 Molecular genetic analyses

Hereditary non-polyposis colorectal cancer (HNPCC) OMIM: 120435, 609310, 614350 Genes: MSH2, MLH1, MSH6, loci 2p21, 3p22.2, 2p16.3 Inheritance: autosomal dominant Indication: positive family history for colon cancer or HNPCC-associated tumors, patient fulfills the updated Bethesda Guidelines (2004) or the classic Amsterdam Criteria Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of MLH1 (approx. 2 wks) 2nd tier: sequencing analysis of MSH2 (approx. 2 wks) 3rd tier: deletion/duplication analysis (MLPA) of MSH2, MLH1 (approx. 2 wks) 4th tier: sequencing analysis of MSH6 (approx. 2 wks) 5th tier: deletion/duplication analysis (MLPA) of MSH6 (approx. 2 wks)

Hereditary Breast/Ovarian cancer (HBOC) OMIM: 114480

BRCA1/2 based OMIM: 113705, 600185 Genes: BRCA1, BRCA2, loci 17q21, 13q12.3, Inheritance: autosomal dominant Indication: suspected hereditary breast/ovarian cancer, positive family history for early onset breast/ovarian cancer, bilateral breast cancer, male family members with breast cancer. Analysis may facilitate therapeutic decision regarding Olaparib treatment. Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of BRCA1, BRCA2 (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of BRCA1, BRCA2 (approx. 2 wks)

31 Molecular genetic analyses

CHEK2 based OMIM: 604373 Genes: CHEK2, locus22q12 Inheritance: autosomal dominant Indication: suspected hereditary breast/ovarian cancer, positive family history for breast/ovarian cancer Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of CHEK2, mutations c.1100delC, c.444+1G>A, c.470T>C) (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of CHEK2 (approx. 2 wks)

RAD51C based OMIM: 613399 Genes: RAD51C, locus17q22 Inheritance: autosomal dominant Indication: suspected hereditary breast/ovarian cancer, positive family history for breast/ovarian cancer Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of RAD51C (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of RAD51C and PALB2 (approx. 2 wks)

PALB2 based OMIM: 610355 Genes: PALB2, locus17q22 Inheritance: autosomal dominant Indication: suspected hereditary breast/ovarian cancer, positive family history for breast/ovarian cancer Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of PALB2 (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of RAD51C and PALB2 (approx. 2 wks)

32 Molecular genetic analyses

Li-Fraumeni syndrome OMIM: 151623 Gene: TP53, locus 17p13.1 Inheritance: autosomal dominant Indication: early onset of tumors, multiple tumors within an individual, and multiple affected family members, variety of tumor types rather than site-specific cancers. Tumors are usually soft tissue sarcomas and osteosarcomas, breast cancer, brain tumors, leukemia, adrenocortical carcinoma Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of TP53 (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of TP53 (approx. 2 wks)

Multiple endocrine neoplasia type I, MEN1 OMIM: 131100 Gene: MEN1, locus 11q13.1 Inheritance: autosomal dominant Indication: tumors of parathyroids, pancreatic islets, duodenal endocrine cells and the anterior pituitary Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of MEN1 (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of MEN1 (approx. 2 wks)

Multiple endocrine neoplasia type II, MEN2 OMIM: 171400 Gene: RET, locus 10q11.2 Inheritance: autosomal dominant Indication: isolated medullary carcinoma of the thyroid (MTC, C-Cell carcinoma), pheochromocytoma, hyperparathyroidism Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of select regions of MEN2 (approx. 2 wks) 2nd tier: sequencing analysis of remaining regions of MEN2 (approx. 2 wks) 3rd tier: deletion/duplication analysis (MLPA) of MEN2 (approx. 2 wks)

33 Molecular genetic analyses

Neurofibromatosis Neurofibromatosis type 1, NF1 OMIM: 162200 Gene: NF1, locus 17q11.2 Inheritance: autosomal dominant Indication: multiple café au lait spots (>5 mm), axillary and inguinal freckling, multiple discrete dermal neurofibromas, iris Lisch nodules Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of NF1 (approx. 3 wks) 2nd tier: deletion/duplication analysis (MLPA) of NF1 (approx. 2 wks)

Neurofibromatosis type 2, NF2 OMIM: 101000 Gene: NF2, locus 22q12.2 Inheritance: autosomal dominant Indication: vestibular schwannoma followed by tinnitus, hearing loss, balance dysfunction, meningiomas, ependymomas, astrocytoma Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of NF2 (approx. 3 wks) 2nd tier: deletion/duplication analysis (MLPA) of NF2 (approx. 2 wks)

34 Molecular genetic analyses

PTEN hamartoma tumor syndrome OMIM: 158350, 153480 Gene: PTEN, locus 10q23.31 Inheritance: autosomal dominant Indication: includes Cowden syndrome (multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, and endometrium), Bannayan-Riley- Ruvalcaba syndrome (multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, and endometrium), PTEN-related Proteus syndrome (PS), and Proteus-like syndrome (congenital malformations and hamartomatous overgrowth of multiple tissues, as well as connective tissue nevi, epidermal nevi) Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of PTEN (approx. 2 wks) 2nd tier: methylation sensitive deletion/duplication analysis (MLPA) of PTEN (approx. 3 wks)

Tuberous sclerosis OMIM: 191100, 613254 Genes: TSC1, TSC2, loci 9q34.31, 16p13.3 Inheritance: autosomal dominant Indication: hamartomas in multiple organs (brain, skin, heart, kidneys, lung), epilepsy, learning difficulties, behavioural problems, autism, renal angiomyolipoma Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of TSC2 (approx. 4 wks) 2nd tier: sequencing analysis of TSC1 (approx. 3 wks) 3rd tier: deletion/duplication analysis (MLPA) of TSC2 (approx. 2 wks) 4th tier: deletion/duplication analysis (MLPA) of TSC1 (approx. 2 wks)

35 Molecular genetic analyses

Von-Hippel-Lindau syndrome, VHL OMIM: 193300 Gene: VHL, locus 3p25.3 Inheritance: autosomal dominant Indication: retinal angioma, cerebellar or spinal cord hemangioblastoma, renal cell carcinoma, pheochromocytoma Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of VHL (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of VHL (approx. 2 wks)

Immune disorders

Celiac disease > please refer to “Gastrointestinal diseases”

HLA-B27 associated diseases OMIM: 142800 Gene: Major Histocompatibility Complex, locus 6p21.3 Inheritance: polygenic/multifactorial Indication: suspected Bechterew disease, spondyloarthropathy, psoriatic arthritis Material: 3-5 ml EDTA blood Methods/TAT: sequence specific PCR (SSP) (approx. 2 wks)

Narcolepsia OMIM: 142857 Gene: Major Histocompatibility Complex, locus 6p21.3 Inheritance: polygenic/multifactorial Indication: hypersomnia, daytime sleepiness, cataplexy Material: 3-5 ml EDTA blood Methods/TAT: sequence specific PCR (SSP) (approx. 2 wks)

36 Molecular genetic analyses

Intersexuality

Congenital adrenal hyperplasia (CAH) > please refer to “Endocrinology”

SRY OMIM: 480000 Gene: SRY, locus Yp11.3 Inheritance: Y-chromosomal Indication: primary amenorrhea, gonadal dysgenesis, suspected XX-males, suspected testicular feminization Material: 3-5 ml EDTA blood Methods/TAT: PCR (approx. 2 wks)

Kidney diseases

Adult dominant polycystic kidney disease (ADPKD) OMIM: 613095, 173900 Genes: PKD1, PKD2, loci 16p13.3, 4q21-23 Inheritance: autosomal dominant Indication: multiple renal and liver cysts, with further complication of hypertension Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of PKD1 (approx. 8 wks) 2nd tier: sequencing analysis of PKD2 (approx. 3 wks) 3rd tier: deletion/duplication analysis (MLPA) of PKD1, PKD2 (approx. 2 wks each)

37 Molecular genetic analyses

Alport syndrome OMIM: 303630, 203780, 104200 Genes: COL4A5, COL4A4, COL4A3, loci Xq22.3, 2q36.3, 2q36.3 Inheritance: X-chromosomal (COL4A5), autosomal dominant/recessive (COL4A4, COL4A3) Indication: micro- or macrohematuria, proteinuria with progression to end stage renal disease, focal thickening or splitting of the glomerular basement membrane, progressive bilateral sensorineural hearing loss, anterior lenticonus Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of COL4A5 (approx. 4 wks) 2nd tier: deletion/duplication analysis (MLPA) of COL4A5 (approx. 2 wks) 3rd tier: sequencing analysis of COL4A3 (approx. 4 wks) 4th tier: sequencing analysis of COL4A4 (approx. 4 wks) 5th tier: deletion/duplication analysis (MLPA) of COL4A4, COL4A3 (approx. 2 wks)

Renal glucosuria OMIM: 233100 Gene: SLC5A2, locus 16p11.2 Inheritance: autosomal dominant, autosomal recessive Indication: glucosuria with no signs of hyperglycemia or tubular dysfunction Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of SLC5A2 (approx. 2 wks)

38 Molecular genetic analyses

Liver diseases

Crigler-Najjar syndrome type I/II OMIM: 143500, 606785 Gene: UGT1A1, locus 2q37 Inheritance: autosomal recessive Indication: Hyperbilirubinemia, congenital familial nonhemolytic jaundice with kernicterus Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: PCR and fragment analysis to detect the TA-expansion in the promoter of UGT1A1 (approx. 2 wks) 2nd tier: sequencing analysis of UGT1A1 (approx. 2 wks)

Hemochromatosis Hemochromatosis type 1 OMIM: 235200 Gene: HFE, locus 6p21.3 Inheritance: autosomal recessive Indication: increased serum ferritin and transferrin saturation, in advanced disease stages liver fibrosis, cirrhosis, bronzed skin, diabetes Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: Real-time PCR (LightCycler technique), detection of the most common mutations p.(Cys282Tyr), p.(His63Asp) and p.(Ser65Cys) (approx. 1 wk) 2nd tier: sequencing analysis of HFE (approx. 2 wks) 3rd tier: deletion/duplication analysis (MLPA) of HFE, SLC40A1, TFR2, HJV, HAMP (approx. 2 wks)

39 Molecular genetic analyses

Hemochromatosis types 2A and 2B (juvenile type) OMIM: 602390 Genes: HAMP, HJV, loci 19q13, 1q21.1 Inheritance: autosomal recessive Indication: severe iron overload occurring typically in the first to third decade of life, increase in skin pigmentation, diabetes, congestive heart failure and/or arrhythmia, arthritis Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of HAMP and HJV (approx. 2 wks, respectively) 2nd tier: deletion/duplication analysis (MLPA) of HFE, SLC40A1, TFR2, HJV, HAMP (approx. 2 wks)

Hemochromatosis type 3 OMIM: 604250 Gene: TFR2, locus 7q22.1 Inheritance: autosomal recessive Indication: severely increased serum ferritin and transferrin saturation, in advanced disease stages liver fibrosis, cirrhosis Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of TFR2 (approx. 3 wks) 2nd tier: deletion/duplication analysis (MLPA) of HFE, SLC40A1, TFR2, HJV, HAMP (approx. 2 wks)

Hemochromatosis type 4 OMIM: 606069 Gene: SLC40A1, locus 2q32.2 Inheritance: autosomal dominant Indication: severe increased serum ferritin and transferrin saturation, in advanced disease stages liver fibrosis, cirrhosis Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of SLC40A1 (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of HFE, SLC40A1, TFR2, HJV, HAMP (approx. 2 wks)

40 Molecular genetic analyses

Hyperbilirubinemia, Gilbert syndrome OMIM: 143500 Gene: UGT1A1, locus 2q37 Inheritance: autosomal recessive Indication: hyperbilirubinemia, congenital familial nonhemolytic jaundice with kernicterus Material: 3-5 ml EDTA blood Methods/TAT: PCR and fragment analysis, detection of the TA-repeat- expansion in the promoter of UGT1A1 (approx. 2 wks)

Wilson disease OMIM: 277900 Gene: ATP7B, locus 13q14.3 Inheritance: autosomal recessive Indication: hepato-, splenomegaly, movement disorders (tremor, poor coordination, loss of fine-motor control, chorea, choreoathetosis) or rigid dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement), Kayser-Fleischer ring Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: Real-time-PCR (LightCycler technique), detection of the most common mutation p.(His1069Gln) (approx. 1 wk) 2nd tier: sequencing analysis of ATP7B (approx. 3 wks) 3rd tier: deletion/duplication analysis (MLPA) of ATP7B (approx. 2 wks)

41 Molecular genetic analyses

Lung diseases

Alpha1-Antitrypsin Deficiency OMIM: 107400 Gene: SERPINA1, locus 14q32.1 Inheritance: autosomal recessive Indication: chronic obstructive pulmonary disease (COPD) in adults, liver disease in children and adults, emphysema, prolonged jaundice, liver disease in adults, manifest as cirrhosis and fibrosis Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: Real-time-PCR (LightCycler technique) for detection of the most common mutation PiS* and PiZ* (approx. 1 wk) 2nd tier: sequencing analysis of SERPINA1 (approx. 2 wks)

Cystic Fibrosis (CF) OMIM: 219700 Gene: CFTR, locus 7q31.2 Inheritance: autosomal recessive Indication: obstructive lung disease, bronchiectasis, exocrine pancreas insufficiency, elevated sweat chloride concentration, meconium ileus Material: 3-5 ml EDTA blood Methods/TAT: Real-time-PCR (LightCycler technique) detection of the most common mutation p.(Phe508del) (approx. 1 wk), panel for 50 common mutations (approx. 2 wks), Sequencing analysis of CFTR (approx. 3 wks), deletion/duplication analysis (MLPA) of CFTR (approx. 2 wks)

Metabolic diseases

Apolipoprotein A1 OMIM: 107680 Gene: APOA1, locus 11q23 Inheritance: autosomal dominant Indication: early identification of at-risk patients for atherosclerosis, assessment of the risk for myocardial infarction and peripheral obstructive disease Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of APOA1 (approx. 2 wks)

42 Molecular genetic analyses

Apolipoprotein B OMIM: 107730 Gene: APOB, locus 2p24 Inheritance: autosomal dominant Indication: dyslipoproteinemia, hypercholesterolemia Material: 3-5 ml EDTA blood Methods/TAT: Real-time-PCR (LightCycler technique) detection of the most common mutations p.(Arg3527Gln), p.(Arg3527Trp), p.(Arg3558Cys) (approx. 1 wk)

Apolipoprotein E OMIM: 107741 Gene: APOE, locus 19q13.2 Inheritance: autosomal dominant Indication: dyslipoproteinemia, hypercholesterinemia, Alzheimer’s disease Material: 3-5 ml EDTA blood Methods/TAT: Real-time-PCR (LightCycler technique) for genotyping of APOE-alleles E2, E3, E4 (approx. 1 wk)

Fabry disease, α-Galactosidase-A deficiency OMIM: 301500 Gene: GLA, locus Xq22 Inheritance: X-linked Indication: males with less than 1% α-galactosidase enzyme activity, periodic crises of severe pain in the extremities (acroparesthesias), appearance of vascular cutaneous lesions (angiokeratomas), hypohidrosis, characteristic corneal and lenticular opacities, and proteinuria, gradual deterioration of renal function to end-stage renal disease Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of GLA (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of GLA (approx. 2 wks)

43 Molecular genetic analyses

Familial hypercholesterolemia OMIM: 143890, 603776 Genes: LDLR, PCSK9, LDLRAP1, loci 19p13.2, 1p32.3. 1p36.11 Inheritance: autosomal dominant (LDLR, PCSK9), autosomal recessive (LDLRAP1) Indication: Hypercholesterolemia, tendinous xanthomas, corneal arcus, premature atherosclerosis and coronary artery disease Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of LDLR (approx. 3 wks) 2nd tier: PCR deletion/duplication analysis (MLPA) of LDLR (approx. 2 wks) 3rd tier: sequencing analysis of PCSK9 (approx. 2 wks) 4th tier: sequencing analysis of LDLRAP1 (approx. 2 wks)

Fructose intolerance > please refer to “Nutrigenetics”

Gaucher disease OMIM: 608013, 230800, 230900, 231000, 231005 Gene: GBA, locus 1q22 Inheritance: autosomal recessive Indication: presence of Gaucher cells (intracellular accumulation of glucosylceramide), hepatosplenomegaly, pancytopenia, neurologic manifestations Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of GBA (approx. 4 wks)

Glucose-6-Phosphate Dehydrogenase Deficiency > please refer to “Hematology”

44 Molecular genetic analyses

Hyperinsulinism severe neonatal type OMIM: 600509, 600937 Genes: ABCC8, KCNJ11, loci 11p15.1, 11p15.1 Inheritance: autosomal recessive Indication: persistent hypoglycemia in the first years of life, severe refractory hypoglycemia in the first 48 hours of life Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of ABCC8 (approx. 4 wks) 2nd tier: sequencing analysis of KCNJ11 (approx. 2 wks) 3rd tier: deletion/duplication analysis (MLPA) of ABCC8 (approx. 2 wks) mild type OMIM: 138130, 138079 Genes: GLUD1, GCK, loci 10q23.3, 7p15-p13 Inheritance: autosomal dominant Indication: persistent hypoglycemia in the first years of life, Hyperinsulinism–hyperammonaemia (HI/HA) syndrome, nonspecific symptoms including seizures, hypotonia, poor feeding and apnea Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of select regions of GLUD1 (approx. 2 wks) 2nd tier: sequencing analysis of remaining regions of GLUD1 (approx. 2 wks) 3rd tier: sequencing analysis of GCK (approx. 2 wks)

Hyperproinsulinemia OMIM: 613370 Gene: INS, locus 11p15.5 Inheritance: autosomal dominant Indication: circulating proinsulin, apparent insulin resistance with hyperglycemia and hyperinsulinemia but good response to insulin treatment Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of INS (approx. 2 wks)

45 Molecular genetic analyses

Lactose intolerance > please refer to “Nutrigenetics”

Maturity-Onset Diabetes of the Young (MODY) OMIM: 606391

MODY1 OMIM: 125850 Gene: HNF4A, locus 20q12-q13.1 Inheritance: autosomal dominant Indication: positive family history of diabetes, early manifestation (before the age of 25), manifestation at first with mild symptoms, no beta cell autoimmunity Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of HNF4A (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of HNF4A, GCK, HNF1A, HNF1B (approx. 2 wks)

MODY2 OMIM: 125851 Gene: GCK, locus 7p15-p13 Inheritance: autosomal dominant Indication: positive family history of diabetes, early manifestation (before the age of 25), manifestation at first with mild symptoms, no beta cell autoimmunity, gestational diabetes Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of GCK (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of HNF4A, GCK, HNF1A, HNF1B (approx. 2 wks)

46 Molecular genetic analyses

MODY3 OMIM: 600496 Gene: HNF1A, locus 12q24.2 Inheritance: autosomal dominant Indication: positive family history of Diabetes, early manifestation (before the age of 25), no beta cell autoimmunity, glucosuria Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of HNF1A (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of HNF4A, GCK, HNF1A, HNF1B (approx. 2 wks)

MODY4 OMIM: 606392 Gene: PDX1, locus 13q12.2 Inheritance: autosomal dominant Indication: positive family history of diabetes, early manifestation (before the age of 25), manifestation at first with mild symptoms, no beta cell autoimmunity, pancreatic abnormalities Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of PDX1 (approx. 2 wks)

MODY5 (Renal cysts and diabetes syndrome, RCAD) OMIM: 137920 Gene: HNF1B, locus 17q12 Inheritance: autosomal dominant Indication: positive family history of diabetes, early manifestation (before the age of 25), manifestation at first with mild symptoms, no beta cell autoimmunity, non-diabetic renal disease, genital malformations and liver dysfunction Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of HNF1B (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of HNF4A, GCK, HNF1A, HNF1B (approx. 2 wks)

47 Molecular genetic analyses

MODY6 OMIM: 606394 Gene: NEUROD1, locus 2q31 Inheritance: autosomal dominant Indication: positive family history of diabetes, early manifestation (before the age of 25), manifestation at first with mild symptoms, no beta cell autoimmunity Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of NEUROD1 (approx. 2 wks)

MODY7 OMIM: 610508 Gene: KLF11, locus 2p25.11 Inheritance: autosomal dominant Indication: positive family history of diabetes, early manifestation (before the age of 25), manifestation at first with mild symptoms, no beta cell autoimmunity Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of KLF11 (approx. 2 wks)

MODY10 OMIM: 610508 Gene: INS, Locus 11p15.5 Inheritance: autosomal dominant Indication: hyperproinsulinemia, positive family history of diabetes, early manifestation (before the age of 25), manifestation at first with mild symptoms, no beta cell autoimmunity Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of INS (approx. 2 wks)

48 Molecular genetic analyses

MCAD Deficiency (Medium-Chain Acyl-CoA Dehydrogenase) OMIM: 201450 Gene: ACADM, locus 1p31 Inheritance: autosomal recessive Indication: positive acylcarnitine screening in newborn, hypoketotic hypoglycemia, vomiting, lethargy triggered by a common illness, seizures, hepatomegaly and acute liver disease, onset typically between three and 24 months of age Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of select regions of ACADM (approx. 1 wk) 2nd tier: sequencing analysis of remaining regions of ACADM (approx. 1 wk)

Neonatal diabetes (permanent/transient) OMIM: 600509, 600937 Genes: ABCC8, KCNJ11, GCK, INS, loci 11p15.1, 11p15.1, 7p15-p13, 11p15.5 Inheritance: autosomal dominant for KCNJ11, autosomal dominant or autosomal recessive for ABCC8 und INS, autosomal recessive for GCK Indication: Hyperglycemia in the first 6 months of life, intrauterine growth retardation, low birth weight, failure to thrive, deficiency of subcutaneous adipose tissue, low C-peptide levels Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of KCNJ11 (approx. 2 wks) 2nd tier: sequencing analysis of ABCC8 (approx. 4 wks) 3rd tier: sequencing analysis of INS (approx. 2 wks) 4th tier: uniparental disomy 6 (UPD6 analysis) (parents’ sample required) (approx. 2 wks) 5th tier: sequencing analysis of GCK (approx. 2 wks) 6th tier: deletion/duplication analysis (MLPA) of HNF4A, GCK, HNF1A, HNF1B (approx. 2 wks)

Obesity (early onset) > please refer to “Endocrinology”

49 Molecular genetic analyses

Osteoporosis OMIM: 166710, 120150, 601769 Genes: COL1A1, VDR, loci 17q21.31-q22, 12q12-q14 Inheritance: polygenic/multifactorial Indication: osteoporosis, genotyping before starting a hormone substitution therapy to assess the risk for osteoporosis Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of the Sp1 polymorphism in the COL1A1 gene (approx. 2 wks), Sequencing analysis of the BsmI polymorphism in the VDR gene (approx. 2 wks)

Phenylketonuria (PKU)/Hyperphenylalaninemia OMIM: 261600, 233910 Gene: PAH, locus 11q22.3 Inheritance: autosomal recessive Indication: positive phenylalanine screening in newborn: plasma phenylalanine concentrations higher than 800 µmol/L, hyperphenylalaninemia Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of PAH (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of PAH (approx. 2 wks)

Porphyria Acute intermittent Porphyria OMIM: 176000 Gene: HMBS, locus 11q23.3 Inheritance: autosomal dominant Indication: acute episodes of abdominal pain, gastrointestinal dysfunction, and neurological disturbances. Attacks may be precipitated by porphyrinogenic drugs, alcohol, infection, starvation, and hormonal changes Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of HMBS (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of HMBS, PPOX (approx. 2 wks)

50 Molecular genetic analyses

Variegate Porphyria OMIM: 176200 Gene: PPOX, locus 1q23.3 Inheritance: autosomal dominant Indication: cutaneous manifestations (increased photosensitivity, blistering, skin fragility with chronic scarring of sun-exposed areas, postinflammatory hyperpigmentation), abdominal pain, passage of dark urine, neuropsychiatric symptoms Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of PPOX (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of HMBS, PPOX (approx. 2 wks)

Porphyria cutanea tarda OMIM: 176100 Gene: UROD, locus 1p34.1 Inheritance: autosomal dominant Indication: light-sensitive dermatitis, chronic ulcerating lesions on skin exposed to sunlight, mechanically fragile skin, hyperpigmentation, hypertrichosis Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of UROD (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of UROD (approx. 2 wks)

Renal glucosuria > please refer to “Kidney diseases”

51 Molecular genetic analyses

Mitochondrial diseases

Chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS), Pearson syndrome OMIM: 530000, 557000 Locus: mitochondrial genome Inheritance: maternal, with variable penetrance Indication: suspected mitochondrial disease, pigmentary retinopathy, progressive external ophthalmoplegia (PEO), sideroblastic anemia and exocrine pancreas dysfunction, ptosis, paralysis of the extraocular muscles (ophthalmoplegia), and variably severe proximal limb weakness, cardiomyopathy Material: muscle biopsy, 3-5 ml EDTA blood Methods/TAT: 1st tier: Long range PCR, detection of deletions (approx. 2 wks) 2nd tier: PCR-RFLP, quantification; detection of the mutation m.3243G>A (approx. 2 wks)

Leber hereditary optic neuropathy (LHON) > please refer to “Eye diseases”

Leigh- / Neuropathy, ataxia, retinitis pigmentosa (NARP syndrome) OMIM: 256000, 551500 Gene: MT-ATP6, mitochondrial genome Indication: Decompensation (often with lactic acidosis) during an intercurrent illness typically associated with psychomotor retardation or regression, neurological features include hypotonia, spasticity, movement disorders (including chorea), cerebellar ataxia, and peripheral neuropathy Material: 3-5 ml EDTA blood Methods/TAT: PCR-RFLP, quantification; detection of the mutations m.8993T>G and m.8993T>C (approx. 2 wks)

52 Molecular genetic analyses

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Diabetes-Deafness syndrome OMIM: 540000 Gene: MT-TL1, mitochondrial genome Inheritance: maternal, with variable penetrance Indication: generalized tonic-clonic seizures that are often associated with stroke-like episodes of transient hemiparesis or cortical blindness, atypical diabetes, deafness, recurrent headaches, cardiac failure, renal failure Material: 3-5 ml EDTA blood Methods/TAT: PCR-RFLP, quantification; detection of the mutation m.3243G>A (approx. 2 wks)

Myoclonic epilepsy associated with ragged-red fibers (MERRF) syndrome OMIM: 545000 Gene: MT-TK, mitochondrial genome Inheritance: maternal, with variable penetrance Indication: myoclonus epilepsy (ragged-red fibers in the muscle biopsy), generalized epilepsy, ataxia, weakness, dementia, hearing loss, short stature, optic atrophy, and cardiomyopathy with Wolff-Parkinson-White syndrome (WPW) Material: 3-5 ml EDTA blood Methods/TAT: PCR-RFLP, quantification; detection of the mutation m.8344A>G (approx. 2 wks)

53 Molecular genetic analyses

Neurodegenerative diseases

For analyses of neurodegenerative diseases we kindly request information regarding the personal and family medical history of the patient or counselee. Please find the respective form on our website.

Autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) OMIM: 169500 Gene: LMNB1, locus 5q23.2 Inheritance: autosomal dominant Indication: onset in the fourth or fifth decade of life, early autonomic abnormalities, pyramidal and cerebellar dysfunction, in neuroimaging symmetric demyelination of the CNS, lack of astrogliosis Material: 3-5 ml EDTA blood Methods/TAT: deletion/duplication analysis (MLPA) of LMNB1 (approx. 2 wks)

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) OMIM: 125310 Gene: NOTCH3, locus 19p13.2-p13.1 Inheritance: autosomal dominant Indication: history of migraine headache, onset of cerebrovascular disease progressing to dementia, diffuse white matter lesions and subcortical infarcts in neuroimaging Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis select regions of NOTCH3 (approx. 2 wks) 2nd tier: sequencing analysis of remaining regions of NOTCH3 (approx. 3 wks) 3rd tier: deletion/duplication analysis (MLPA) of NOTCH3 (approx. 2 wks)

54 Molecular genetic analyses

Friedreich Ataxia OMIM: 229300 Gene: FXN, locus 9q21.11 Inheritance: autosomal recessive Indication: progressive gait and limb ataxia, limb muscle weakness, absent lower limb reflexes, extensor plantar responses, dysarthria, and decreased vibratory sense and proprioception, onset between 5 and 25 years Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: PCR, fragment analysis for determination of the GAA-repeat length of the FXN gene (approx. 3 wks) 2nd tier: sequencing analysis of FXN (approx. 2 wks) 3rd tier: deletion/duplication analysis (MLPA) of FXN (approx. 2 wks)

Huntington disease OMIM: 143100 Gene: HTT, locus 4p16.3 Inheritance: autosomal dominant Indication: hyperkinesia, choreatic movements, disturbance of speech, dementia Material: 3-5 ml EDTA blood Methods/TAT: PCR, fragment analysis: identification of the CAG-repeat length / CGG repeat length of HTT (approx. 2 wks)

Spinocerebellar ataxias Spinocerebellar ataxia type 1 (SCA1) OMIM: 164400 Gene: ATXN1, locus 6p22.3 Inheritance: autosomal dominant Indication: cerebellar and upper motor neuron signs, extensor plantar responses, onset in the third or fourth decade of life Material: 3-5 ml EDTA blood Methods/TAT: PCR, fragment analysis: identification of the CAG-repeat length of ATXN1 (approx. 2 wks)

55 Molecular genetic analyses

Spinocerebellar ataxia type 2 (SCA2) OMIM: 183090 Gene: ATXN2, locus 12q24.12 Inheritance: autosomal dominant Indication: progressive cerebellar ataxia, nystagmus, slow saccadic eye movements, ophthalmoparesis, parkinsonism, presence of pyramidal signs, onset in the fourth decade Material: 3-5 ml EDTA blood Methods/TAT: PCR, fragment analysis: identification of the CAG-repeat length of ATXN2 (approx. 2 wks)

Spinocerebellar ataxia type 3 (SCA3), Machado-Joseph disease (MJD) OMIM: 109150 Gene: ATXN3, locus 14q32.12 Inheritance: autosomal dominant Indication: progressive cerebellar ataxia, dystonic-rigid syndrome, spasticity, and ocular movement abnormalities Material: 3-5 ml EDTA blood Methods/TAT: PCR, fragment analysis: identification of the CAG-repeat length of ATXN3 (approx. 2 wks)

Spinocerebellar ataxia type 6 (SCA6) OMIM: 183086 Gene: CACNA1A, locus 19p13.13 Inheritance: autosomal dominant Indication: gait unsteadiness, stumbling, and imbalance, slowly progressive cerebellar ataxia, dysarthria, and nystagmus, dysarthria, upper-limb incoordination, intention tremor, dysarthria, dysphagia, onset in the fourth decade Material: 3-5 ml EDTA blood Methods/TAT: PCR, fragment analysis: identification of the CAG-repeat length of CACNA1A (approx. 2 wks)

56 Molecular genetic analyses

Spinocerebellar ataxia type 7 (SCA7) OMIM: 183086 Gene: ATXN7, locus 3p14.1 Inheritance: autosomal dominant Indication: progressive cerebellar ataxia, dysarthria, dysphagia, cone-rod and retinal dystrophy with progressive central visual loss resulting in blindness Material: 3-5 ml EDTA blood Methods/TAT: PCR, fragment analysis: identification of the CAG-repeat length of ATXN7 (approx. 2 wks)

Neuromuscular diseases /Neuropathies

Charcot-Marie-Tooth disease (CMT) Charcot-Marie-Tooth disease type 1A (CMT1A) OMIM: 118220 Gene: PMP22, locus 17p11.2 Inheritance: autosomal dominant Indication: demyelinating peripheral neuropathy characterized by distal muscle weakness and atrophy, sensory loss, and slow nerve conduction velocity, pes cavus foot deformity, bilateral foot drop, age of onset 5-25 years Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: deletion/duplication analysis (MLPA) of PMP22 (approx. 2 wks) 2nd tier: sequencing analysis of PMP22 (approx. 2 wks)

57 Molecular genetic analyses

Charcot-Marie-Tooth disease type 1B (CMT1B) OMIM: 118200 Gene: MPZ, locus 1q23.3 Inheritance: autosomal dominant Indication: clinically similar to CMT1A, albeit with bimodal curve in nerve conduction velocity (NCV) and later age of onset, and more frequent hearing loss and pupillary abnormalities Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of MPZ (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of MPZ, MFN2 (approx. 2 wks)

Charcot-Marie-Tooth disease type 2A (CMT2A) OMIM: 609260 Gene: MFN2, locus 1p36.22 Inheritance: autosomal dominant Indication: axonal peripheral sensorimotor neuropathy with early and more severe involvement of the lower extremities than the upper extremities, distal upper-extremity involvement as the neuropathy progresses, more prominent motor deficits than sensory deficits, normal or only slightly decreased nerve conduction velocities (NCVs), postural tremor Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of MFN2 (approx. 3 wks) 2nd tier: deletion/duplication analysis (MLPA) of MPZ, MFN2 (approx. 2 wks)

58 Molecular genetic analyses

Charcot-Marie-Tooth disease type X1 (CMTX1) OMIM: 302800 Gene: GJB1, locus Xq13.1 Inheritance: X-chromosomal dominant Indication: clinically similar to CMT1A, nerve conduction velocity (NCV) nearly normal to moderately slow, moderate to severe motor and sensory neuropathy in affected males and usually mild to no symptoms in carrier females Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of GJB1 (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of GJB1 (approx. 2 wks)

Hereditary neuropathy, with liability to pressure palsies (HNPP) OMIM: 162500 Gene: PMP22, locus 17p11.2 Inheritance: autosomal dominant Indication: repeated focal pressure neuropathies such as carpal tunnel syndrome, peroneal palsy with foot drop, age of onset usually in the second or third decade of life Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: deletion/duplication analysis (MLPA) of PMP22 (approx. 2 wks) 2nd tier: sequencing analysis of PMP22 (approx. 2 wks)

Muscular dystrophy type Duchenne/Becker (DMD/BMD) OMIM: 310200, 300376 Gene: DMD, locus Xp21 Inheritance: X-linked recessive Indication: progressive proximal muscular dystrophy, pseudohypertrophy, increase in serum concentration of creatine phosphokinase (CK), myofiber degeneration with fibrosis and fatty infiltration in muscle biopsy, cardiomyopathy Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: deletion/duplication analysis (MLPA) of DMD (approx. 2 wks) 2nd tier: sequencing analysis of DMD (approx. 4 wks)

59 Molecular genetic analyses

Myotonic dystrophy Myotonic dystrophy type 1, Steinert disease OMIM: 160900 Gene: DMPK, locus 19q13.2-q13.3 Inheritance: autosomal dominant Indication: muscle weakness and wasting, myotonia, muscular dystrophy, cataract, hypogonadism and often cardiac conduction abnormalities Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: PCR and fragment analysis; determination of the CTG- repeat length of DMPK (short repeat ranges) (approx. 2 wks) 2nd tier: Southern blot; determination of the CTG-repeat length of DMPK (long repeat ranges) (approx. 3 wks)

Myotonic dystrophy type 2 / proximal myotonic myopathy (PROMM) OMIM: 602668 Gene: CNBP, locus 3q21 Inheritance: autosomal dominant Indication: myotonia and muscle dysfunction, muscular dystrophy, cataract, onset usually in the third decade of life Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: PCR and fragment analysis; determination of the CCTG-repeat length of CNBP (short repeat ranges) (approx. 2 wks) 2nd tier: Southern blot; determination of the CCTG-repeat length of CNBP (long repeat ranges) (approx. 3 wks)

60 Molecular genetic analyses

Spinal and Bulbar Muscular Atrophy (SBMA), Kennedy disease OMIM: 313200 Gene: AR, locus Xq11-q12 Inheritance: X-linked recessive Indication: proximal muscle weakness, muscle atrophy, fasciculations, gynecomastia, testicular atrophy, and reduced fertility as a result of mild androgen insensitivity Material: 3-5 ml EDTA blood Methods/TAT: PCR, fragment analysis; determination of the CAG-repeat length of AR (approx. 2 wks)

Spinal muscular atrophy types I/II/III OMIM: 253300, 253550, 253400 Gene: SMN1, locus 5q12.2-q13.3 Inheritance: autosomal recessive Indication: suspected Werdnig-Hoffmann disease or Kugelberg- Welander disease, severe proximal progressive muscle weakness, hypotonia, psychomotor delay, joint laxity, onset ranging from before birth to adolescence or young adulthood Material: 3-5 ml EDTA blood Methods/TAT: deletion/duplication analysis (MLPA) of SMN1 and SMN2 (approx. 2 wks)

61 Molecular genetic analyses

Nutrigenetics

Celiac disease > please refer to “Gastrointestinal diseases”

Fructose intolerance OMIM: 229600 Gene: ALDOB, locus 9q22.3 Inheritance: autosomal recessive Indication: nausea and abdominal pain after eating fruits and fructose/ sucrose-containing foods, fructose-/ saccharose-intolerance; hypoglycemia, vomiting, nonspecific liver dysfunction Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of select regions of ALDOB (approx. 2 wks) 2nd tier: sequencing analysis of remaining regions of ALDOB (approx. 2 wks) 3rd tier: deletion/duplication analysis (MLPA) of ALDOB (approx. 2 wks)

Lactose intolerance OMIM: 223100 Gene: LCT, locus 2q21 Inheritance: autosomal recessive Indication: lactose intolerance, abdominal symptoms, including stomach cramps, bloating and flatulence after intake of lactose- containing food Material: 3-5 ml EDTA blood Methods/TAT: Real-time-PCR (LightCycler technique); detection of the polymorphism -13910C>T of LCT (approx. 1 wk)

62 Molecular genetic analyses

Pancreatic diseases

Hereditary pancreatitis OMIM: 167800 Genes: PRSS1, SPINK1, CFTR, loci 7q35, 5q32, 7q31.2 Inheritance: autosomal dominant, incomplete penetrance (PRSS1), autosomal recessive, incomplete penetrance (SPINK1), autosomal recessive (CFTR) Indication: recurrent episodes of pancreatic attacks, which can progress to chronic pancreatitis, abdominal pain, nausea and vomiting, elevated amylase and lipase serum concentrations in children, obstructive lung disease, bronchiectasis, exocrine pancreas insufficiency, elevated sweat chloride concentration, meconium ileus Material: 3-5 ml EDTA blood Methods/TAT: PCR, sequencing analysis of exons 2 and 3 of PRSS1 (approx. 2 wks), Sequencing analysis of SPINK1 (approx. 2 wks), panel for 50 common mutations (approx. 2 wks), sequencing analysis of CFTR (approx. 2 wks), deletion/ duplication analysis (MLPA) of CFTR (approx. 2 wks)

Periodic fever

Chronic neurologic cutaneous and articular syndrome (CINCA) / neonatal onset multisystemic inflammatory disease (NOMID) OMIM: 607115 Gene: NLRP3, locus 1q44 Inheritance: autosomal dominant Indication: severe chronic inflammatory disease of early onset, cutaneous symptoms, central nervous system involvement and arthropathy Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of NLRP3 (approx. 2 wks)

63 Molecular genetic analyses

Familial cold autoinflammatory syndrome (FCAS) OMIM: 120100 Gene: NLRP3, locus 1q44 Inheritance: autosomal dominant Indication: cold urticaria, recurrent attacks of a maculopapular rash associated with arthralgias, myalgias, fever and chills, and swelling of the extremities after exposure to cold Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of NLRP3 (approx. 2 wks)

Familial mediterranean fever (FMF) OMIM: 249100 Gene: MEFV, locus 16p13 Inheritance: autosomal recessive Indication: recurrent short episodes of inflammation and serositis including fever, peritonitis, synovitis, pleuritis, and, rarely, pericarditis and meningitis, amyloidosis Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of select regions of MEFV (approx. 2 wks) 2nd tier: sequencing analysis of remaining regions of MEFV (approx. 2 wks) 3rd tier: deletion/duplication analysis (MLPA) of MEFV (approx. 2 wks)

Hyper-IgD syndrome (HIDS) OMIM: 260920 Gene: MVK, locus 12q24 Inheritance: autosomal recessive Indication: recurrent febrile attacks with no fixed periodicity, accompanied by abdominal pain and arthralgia, increased IgD levels (>100 IU/ml) Material: 3-5 ml EDTA blood Methods/TAT: PCR, sequencing analysis of MVK (approx. 2 wks)

64 Molecular genetic analyses

Muckle-Wells syndrome OMIM: 191900 Gene: NLRP3, locus 1q44 Inheritance: autosomal dominant Indication: episodic skin rash, arthralgias, and fever associated with late-onset sensorineural deafness and renal amyloidosis Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of NLRP3 (approx. 2 wks)

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), familial Hibernian fever OMIM: 142680 Gene: TNFRSF1A, locus 12p13.2 Inheritance: autosomal dominant Indication: episodes of autoinflammation usually associated with fever, abdominal pain, myalgia, exanthema, arthralgia/arthritis and ocular involvement Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: PCR, sequencing analysis of select regions of TNFRSF1A (approx. 2 wks) 2nd tier: PCR, sequencing analysis of remaining regions of TNFRSF1A (approx. 2 wks)

Pharmacogenetics

5- Fluorouracil (5FU)- toxicity OMIM: 274270 Gene: DPYD, locus 1p22 Inheritance: autosomal dominant Indication: risk assessment for toxicity for cancer patients for whom 5‑Fluorouracil-based chemotherapy is planned Material: 3-5 ml EDTA blood Methods/TAT: Real-time-PCR (LightCycler technique) to detect the exon 14 skipping mutation (c.1905+1G>A) of DPYD (approx. 2-3 days)

65 Molecular genetic analyses

Statin-induced myopathy (SLCO1B1), haplotype SLCO1B1*5 OMIM: 604843 Gene: SLCOB1, locus 12p12.1 Inheritance: polygenic/multifactorial Indication: risk assessment for myopathy during treatment with statins Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of SLCO1B1, detection of haplotype SLCO1B1*5 (approx. 2 wks)

Thiopurin S-Methyltransferase Deficiency OMIM: 610460 Gene: TPMT, locus 6p22.3 Inheritance: autosomal dominant Indication: risk assessment for toxicity for cancer patients for whom azathioprine, 6-mercaptopurine and 6-thioguanine based chemotherapy is planned Material: 3-5 ml EDTA blood Methods/TAT: Real-time-PCR (LightCycler technique; detection of the mutations c.238G>C, c.460G>A und c.719A>G, haplotypes TPMT*1, TPMT*2, TPMT*3A, TPMT*3B, TPMT*3C) (approx. 2-3 days)

UDP-Glucuronosyl-Transferase OMIM: 191740 Gene: UGT1A1, locus 2q37 (see also Hyperbilirubinemia, Gilbert syndrome) Inheritance: autosomal recessive Indication: risk assessment for toxicity for cancer patients for whom irinotecan based chemotherapy is planned Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: PCR and fragment analysis to detect the TA-expansion in the promoter of UGT1A1 (approx. 2 wks) 2nd tier: sequencing analysis of UGT1A1 (approx. 2 wks)

66 Molecular genetic analyses

Short stature

Disproportionate short stature Achondroplasia OMIM: 100800 Gene: FGFR3, locus 4p16.3 Inheritance: autosomal dominant Indication: disproportionate short stature, short limbs, frontal bossing, mid face hypoplasia, lumbar lordosis, short fingers Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of FGFR3, detection of the mutations c.1138G>A and c.1138G>C (approx. 2 wks) 2nd tier: sequencing analysis of remaining regions of FGFR3 (approx. 2 wks)

Hypochondroplasia OMIM: 146000 Gene: FGFR3, locus 4p16.3 Inheritance: autosomal dominant Indication: disproportionate short stature, slight lumbar lordosis, reduced extensibility of the elbows, symptoms similar to achondroplasia but milder appearance Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of FGFR3; detection of the mutations c.1620C>A, c.1620C>G, c.1619A>C and c.1619A>G (approx. 2 wks) 2nd tier: sequencing analysis of remaining regions of FGFR3 (approx. 2 wks)

Thanatophoric dysplasia OMIM: 187600 Gene: FGFR3, locus 4p16.3 Inheritance: autosomal dominant Indication: usual perinatal or neonatal lethal condition; short ribs and narrow thorax, macrocephaly, hypotonia, type I characterized by micromelia and bent femurs, type II characterized by micromelia, straight femurs, cloverleaf skull deformity Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of FGFR3 (approx. 2 wks)

67 Molecular genetic analyses

SHOX deficiency OMIM: 312865 Gene: SHOX/SHOXY, locus Xpter-p22.32 / Ypter-p11.2 Inheritance: pseudo-autosomal dominant Indication: idiopatic short stature, Leri-Weill syndrome, Langer mesomelic dysplasia Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: deletion/duplication analysis (MLPA) of SHOX and PAR1 (approx. 2 wks) 2nd tier: sequencing analysis of SHOX (approx. 2 wks)

Silver-Russell syndrome (SRS) > please refer to “Complex syndromes”

Thrombophilia / Atherosclerosis

Angiotensin converting enzyme (ACE) OMIM: 106180 Gene: ACE, locus 17q23 Inheritance: polygenic/multifactorial Indication: risk assessment for coronary artery disease, hypertension Material: 3-5 ml EDTA blood Methods/TAT: PCR, genotyping of the deletion/insertion polymorphism in intron 16 of ACE (ACE I/D) (approx. 2 wks)

Antithrombin III deficiency (AT3D) OMIM: 613118 Gene: SERPINC1, locus 1q25.1 Inheritance: autosomal dominant Indication: risk assessment for venous thromboembolic disease, severe thrombophilia Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of SERPINC1 (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of SERPINC1 (approx. 2 wks)

68 Molecular genetic analyses

ß-Fibrinogen OMIM: 134830 Gene: FGB, Locus 4q28 Inheritance: polygenic/multifactorial Indication: elevated fibrinogen levels Material: 3-5 ml EDTA blood Methods/TAT: PCR-RFLP, genotyping of the polymorphism c.-455G>A in the FGB-gene (approx. 2 wks)

Factor V, APC resistance OMIM: 188055 Gene: F5, locus 1q23 Inheritance: autosomal dominant Indication: thrombophilia due to activated protein C resistance, family history of thrombosis Material: 3-5 ml EDTA blood Methods/TAT: Real-time-PCR (LightCycler technique), genotyping of the Leiden mutation p.(Arg534Gln), legacy p.Arg506Gln, of F5 Sequencing analysis of F5 (approx. 1 wk), genotyping of the mutation p.(His1327Arg), legacy H1299R, HR2 haplotype (approx. 2 wks)

Factor XIII, A1 subunit OMIM: 134570 Gene: F13A1, locus 6p25-24 Inheritance: polygenic/multifactorial Indication: assessment of the protective effect of the variant p.(Val35Leu), legacy V34L, against myocardial infarction Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of F13A1, genotyping of the variant p.(Val35Leu), legacy V34L (approx. 2 wks)

69 Molecular genetic analyses

Glycoprotein Ia OMIM: 192974 Gene: ITGA2, locus 5q23-q31 Inheritance: polygenic/multifactorial Indication: risk assessment for venous thromboembolic disease Material: 3-5 ml EDTA blood Methods/TAT: Real-time-PCR (LightCycler technique), genotyping of the polymorphism c.759C>T (legacy c.807C>T) of ITGA2 (approx. 1 wk)

Glycoprotein IIIa OMIM: 173470 Gene: ITGB3, locus 17q21.32 Inheritance: polygenic/multifactorial Indication: risk assessment for venous thromboembolic disease Material: 3-5 ml EDTA blood Methods/TAT: Real-time-PCR (LightCycler technique), genotyping of the polymorphism HPA-1a/1b c.176C>T; p.Leu59Pro (legacy c.1565C>T; p.Leu33Pro) of ITGB3 (approx. 1 wk)

Homocysteinemia OMIM: 236250 Gene: MTHFR, locus 1p36.3 Inheritance: autosomal dominant Indication: homocystinuria, homocysteinemia Material: 3-5 ml EDTA blood Methods/TAT: Real-time-PCR (LightCycler technique), genotyping of the mutations p.(Ala222Val) and p.(Glu429Ala) of MTHFR (approx. 1 wk)

70 Molecular genetic analyses

Plasminogen-Activator-Inhibitor type 1, PAI1 OMIM: 173360 Gene: SERPINE1, locus 7q21.3-22 Inheritance: polygenic/multifactorial Indication: risk assessment for thrombophilia, usually in combination with F5 and F2 genotyping Material: 3-5 ml EDTA blood Methods/TAT: Real-time-PCR (LightCycler technique), genotyping of the polymorphism 4G/5G in the promotor region of SERPINE1 (approx. 1 wk)

Prothrombin, Factor II OMIM: 176930 Gene: F2, locus 11q11 Inheritance: autosomal dominant Indication: risk assessment for thrombophilia Material: 3-5 ml EDTA blood Methods/TAT: Real-time-PCR (LightCycler technique) genotyping of the mutation G20210A in the 3´UTR of F2 (approx. 1 wk)

Protein C deficiency OMIM: 176860, 612304 Gene: PROC, locus 2q14.3 Inheritance: autosomal recessive and autosomal dominant Indication: severe thrombophilia Material: 3-5 ml EDTA blood Methods/TAT: 1st tier: sequencing analysis of PROC (approx. 2 wks) 2nd tier: deletion/duplication analysis (MLPA) of PROC (approx. 2 wks)

Protein C receptor, PROCR OMIM: 600646 Gene: PROCR, locus 20q11.22 Inheritance: polygenic/multifactorial Indication: venous thromboembolism and myocardial infarction Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of PROCR (approx. 2 wks)

71 Molecular genetic analyses

Protein Z deficiency OMIM: 614024 Gene: PROZ, locus 13q34 Inheritance: polygenic/multifactorial Indication: thrombophilia Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of PROZ (approx. 2 wks)

Protein Z dependent protease inhibitor OMIM: 605271 Gene: SERPINA10, locus 14q32.13 Inheritance: polygenic/multifactorial Indication: venous thromboembolism and myocardial infarction Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of SERPINA10 (approx. 2 wks)

Thrombomodulin defect OMIM: 614486 Gene: THBD, locus 20p11.21 Inheritance: polygenic/multifactorial Indication: venous thromboembolism and myocardial infarction Material: 3-5 ml EDTA blood Methods/TAT: Sequencing analysis of THBD (approx. 2 wks)

72 Kinship Analyses

Uniparental disomies

Uniparental disomies 2, 6, 7, 11, 14, 15 OMIM: UPD6 601410, UPD7 180860, UPD11 130650, UPD14 608149, UPD15 105830, 176270 Indication: Beckwith-Wiedemann syndrome; Silver-Russell syndrome; PWS/AS; neonatal diabetes Material: 3-5 ml EDTA blood of patient and both parents Methods/TAT: microsatellite analysis, segregation analysis (approx. 2 wks) Loci: 20 polymorphic STRs in the human genome Purpose: Paternity and/or maternity testing, monozygotic/dizygotic twins Material: 3-5 ml EDTA blood or at least two buccal swabs Methods/TAT: PCR, microsatellite (STR) analysis (approx. 2-3 wks)

Legal or personal reports

73 Cytogenetics and molecular cytogenetics

Prenatal chromosome diagnostics

Chromosome analysis from amniotic fluid Indication: advanced maternal age, conspicuous ultrasound and/ or biochemical findings, fetal malformation, parental chromosomal structural changes, preceding abortion or stillbirth, birth of children with chromosomal changes, birth of children with congenital malformations, mutagen exposure before or during pregnancy, psychological distress, neural tube defects, viral infections of the embryo Material: 10-15 ml amniotic fluid, sealed original syringe, not centrifuged Methods/TAT: Cell culture of amniotic cells, preparation of chromosomes, G-banded chromosome analysis (approx. 1-2 weeks). In case of normal cytogenetic findings and abnormal fetal ultrasound a chromosomal microarray analysis with the platform Infinium CytoSNP-850K (Illumina) may be carried out (approx. 1-2 wks).

Figure: Inconspicuous male chromosomes (karyotype: 46,XY)

74 Cytogenetics and molecular cytogenetics Cytogenetics and molecular cytogenetics

Chromosome analysis from chorionic villi sampling (CVS) Indication: early prenatal diagnostics (from the 10th week of pregnancy), advanced maternal age, preceding abortion or stillbirth, parental chromosomal structural changes, conspicuous first-trimester-screening, conspicuous ultrasound findings, birth of children with congenital malformations, mutagen exposure before or during pregnancy, psychological distress, known familial gene mutations Material: 10-20 mg chorionic villi, in transport medium or in sterile heparin-added physiological NaCl-solution Methods/TAT: direct preparation or preparation after 24 hr-culture, long-term culture to rule out a placenta-fetus-mosaic und to assess the fine structure of chromosomes, preparation of chromosomes, G-banded chromosome analysis (rapid diagnosis after 6-24 hrs, final diagnosis 1-2 weeks) In case of normal cytogenetic findings and abnormal fetal ultrasound, a chromosomal microarray analysis with the platform Infinium CytoSNP-850K (Illumina) may be carried out (approx. 1-2 wks).

Figure: Male chromosomes with an additional chromosome 13 (trisomy 13) (karyotype: 47,XY,+13)

75 Cytogenetics and molecular cytogenetics

Postnatal chromosome diagnostics

Chromosome analysis from peripheral lymphocytes Indication: involuntary childlessness, sterility, suspicion of gonosomal chromosomal changes, habitual miscarriages, birth of children with chromosomal abnormalities, conspicuous prenatal karyotype of the unborn child, suspicion of a dysmorphic syndrome indicated by prenatal ultrasound findings, known familial chromosomal changes Material: 2-5 ml heparin-blood Methods/TAT: culture of peripheral T-lymphocytes (48 hrs, 72 hrs), G-banded chromosome analysis (approx. 1-2 wks)

Figure: Inconspicuous female chromosomes (karyotype: 46,XX)

76 Cytogenetics and molecular cytogenetics

Chromosome analysis from products of conception Indication: involuntary childlessness, miscarriages after IVF/ICSI, preceding miscarriages, known parental chromosomal changes, preceding births of children with chromosomal changes Material: products of conception, 2-5 ml EDTA-blood from the mother Methods/TAT: cell culture, G-banded chromosome analysis. If the analysis reveals a normal female karyotype, microsatellite analysis is performed to determine whether 46,XX results are truly representative of the fetal karyotype. In case of cell culture failure, a chromosomal microarray on fetal DNA is performed. If necessary, fluorescence in situ hybridization (FISH) with specific probes on native embryonic cells is used for exclusion of polyploidy (approx. 1-8 wks).

Left figure: Verification of a trisomy 22 after fluorescence in situ hybridization in native cells of chorionic villi preparations from products of conception (chromosome 22: gold, chromosome 13: red, chromosome 21: green, chromosome 16: aqua).

Right figure: Male chromosomes with a trisomy 20 (karyotype: 47,XY,+20)

77 Cytogenetics and molecular cytogenetics

Molecular cytogenetics

Fluorescence in situ hybridization (FISH) Rapid prenatal diagnostics Loci: 13q14 (RB1), 21q22 (DSCR), 18p11-q11 (D18Z1), Xp11-q11 (DXZ1), Yp11-q11 (DYZ3) Indication: advanced maternal age, conspicuous ultrasound and/or biochemical findings, psychological distress Material: native amniotic cells Methods/TAT: preparation of native amniotic cells, prescreening for the most frequent aneuploidies with fluorescence in situ hybridization using specific probes for chromosomes 13, 18, 21, X, and Y (approx. 4-24 hrs)

The prenatal FISH test is always performed in combination with conventional chromosome analysis.

Left figure: Inconspicuous signal pattern in a native amniotic cell after a fluorescence in situ hybridization with specific probes for chromosomes 21 (red) and 13 (green)

Right figure: Inconspicuous male signal pattern after hybridization with specific probes for chromosomes 18 (aqua), Y (red), and X (green)

78 Cytogenetics and molecular cytogenetics

Microdeletion-diagnostics, screening for mosaicism, chromosome “painting“ Loci: depending on the indication and preliminary findings, e.g. Wolf-Hirschhorn-syndrome (4p16.3), Cri-du-Chat (5p15.2), Williams-Beuren syndrome (7q11), Prader-Willi / Angelman syndrome (15q11-q13), Lissencephaly / Miller-Dieker syndrome (17p13.3), Smith-Magenis syndrome (17p11.2), DiGeorge / Catch22 syndrome (22q11.2), Kallmann syndrome (Xp22.3), sex reversal (Yp11.23), X-linked ichthyosis, and others on request Indication: suspected microdeletion syndrome, chromosomal translocation, exclusion of mosaics, complex chromosomal rearrangements, detection of a familial microdeletion (e.g. chromosomal rearrangement with participation of the chromosome region critical for Down syndrome) Material: heparin blood, amniotic fluid, chorionic villi, products of conception, buccal swabs, skin biopsy Methods/TAT: cell culture, preparation of chromosomes, hybridization with appropriate fluorescence-marked DNA-probes, fluorescence microscopy (approx. 1-5 days).

Left figure: Confirmation of a deletion of the SHOX-region (red signal) in the short arm of one of the two X chromosomes using FISH

Right figure: Presentation of a balanced reciprocal translocation between chromosomes 4 and 6 after FISH with a „painting“ probe specific for chromosome 4 (green signal)

79 Cytogenetics and molecular cytogenetics

Subtelomere analysis Loci: FISH probes: Subtelomere-regions of all chromosomes Indication: Suspicion of chromosomal dysmorphic syndrome of unclear origin, developmental retardation, mental retardation, phenotypic features, habitual miscarriages Material: 2-5 ml heparin blood Methods/TAT: Fluorescence in situ hybridization with subtelomere-specific probes (whole panel) always in context with a conventional chromosome analysis, single probe diagnostics on request (approx. 1-2 wks)

Figure: Confirmation of a deletion in the subtelomeric region of the long arm of one chromosome 4 (red signal in 4q)

80 Chromosomal microarray diagnostics

Indication: Mental retardation, pre- and postnatal growth retardation, specific growth anomalies (e.g. microcephaly, microsomia or macrocephaly, macrosomia), two or more facial dysmorphies (e.g. hypertelorism, nose and ear anomalies), congenital anomalies (e.g. heart defect, hand defects, hypospadias), cerebral seizures, behavioural abnormalities Material: 3-5 ml fresh EDTA blood; To validate detected imbalances an additional heparin blood sample (3-5 ml) might be needed; To clarify the origin of a detected imbalance, parental blood samples (3-5 ml heparin or EDTA blood) might be necessary. Methods/TAT: high-resolution chromosomal microarray (Infinium CytoSNP- 850K, Illumina), detection of genomic imbalances and copy-neutral loss of heterozygosity (LOH) events in the whole genome (approx. 2-8 wks)

Figure: ideogram of chromosome 19. No genomic imbalance but the B-allele frequency indicates a loss-of-heterozygosity (LOH).

81 Quality assurance

Since the founding of our laboratory in the year 2000 we have established quality control procedures, which not only comply with the highest quality standards but also guarantee a continuous improvement of our quality procedures. An essential part of our quality assurance is the regular participation in internal and external quality assessment schemes. In this way, quality, safety and reliability of our services are assured to be on the highest level for the benefit of the patients.

Molecular Genetics The department of Molecular Genetics successfully participates in external quality assessment schemes of the European Molecular Genetics Quality Network (EMQN), the Cystic Fibrosis European Network, the Reference Institute for Bioanalytics (RfB), and the Deutsche Gesellschaft für Abstammungsbegutachtung (DGAB). Apart from that we carry out interlaboratory comparisons with cooperating laboratories for certain analyses for which external quality assessment is not available.

11p Imprinting disorders (BWS/SRS) Fragile X- syndrome 5-Flurouracil (5FU)-toxicity (DPYD) Friedreich ataxia Alpha1-Antitrypsin Deficiency (SER- Gaucher disease PINA1) Gilbert syndrome Alport syndrome Glucose-6-Phosphate Dehydrogenase Angiotensin converting enzyme (ACE) Deficiency Apolipoprotein B Glycoprotein Ia Apolipoprotein E Glycoprotein IIIa Autosomal dominant polycystic kidney Hemochromatosis disease Hemophilia A and B Breast-ovarian cancer, familial Hereditary non-polyposis colon cancer Celiac disease (HNPCC) CADASIL Hereditary pancreatitis Charcot-Marie-Tooth disease Hereditary recurrent fevers Congenital adrenal hyperplasia HLAB27 Cystic fibrosis Homocysteinemia (MTHFR) DiGeorge syndrome Huntington disease DNA-sequencing Inflammatory bowel (Crohn) disease Duchenne muscular dystrophy (NOD2) Ehlers-Danlos syndrome Kinship analyses Fabry disease Lactose intolerance (LCT) Familial adenomatous polyposis colon Leber’s hereditary optic neuropathy cancer Marfan syndrome Factor V Monogenic diabetes (MODY) Factor XIII Multiple Endocrine Neoplasia Type 1 and 2 Familial hypercholesterolemia Myotonic dystrophy type I FGFR3 related disorders Neurofibromatosis type 1

82 Quality assurance

Noonan syndrome Spinal muscular atrophy Osteogenesis Imperfecta Spinocerebellar ataxias Osteoporosis ß-Fibrinogen Phenylketonuria Thalassemia, α- and ß- Plasminogen-Activator-Inhibitor type Thiopurin S-Methyltransferase Defi- 1, PAI1 ciency (TPMT) Porphyrias Von-Hippel-Lindau syndrome Prader Willi / Angelman syndrome Wilson disease Prothrombin (Factor II) Y-chromosome microdeletions Short Stature Homeobox gene (SHOX deficiency)

Cytogenetics and Molecular Cytogenetics The department of cytogenetics and molecular cytogenetics successfully participates in external quality assessment schemes of the Cytogenetic External Quality Assessment Service (CEQAS) and the BVDH e.V. (Association of German Human Genetics Laboratories e.V.).

CEQAS Amniotic Fluid CEQAS CVS CEQAS Products of Conception (G-banded only) CEQAS Blood CEQAS FISH rapid aneuploidy CEQAS Constitutional microarray analysis - Postnatal CEQAS Products of Conception BVDH Labororientierte QS Postnatal BVDH Labororientierte QS Pränatal (Amnion)

DAkkS – Accreditation Our Laboratory is accredited by the “DAkkS” (Deutsche Akkreditierungsstelle GmbH). All molecular Ggnetic and cytogenetic examinations are accredited according to DIN EN ISO 15189:2014. All examinations for kinship analyses are accredited according to DIN EN ISO/IEC 17025:2005.

D-PL-13225-01-00D-PL-13225-01-00 D-ML-13225-01-00D-ML-13225-01-00 83 Index

17-alpha-Hydroxylase deficiency...... 24 anosmia...... 16 21-Hydroxylase deficiency...... 23 anterior lenticonus...... 39 3-beta-Hydroxysteroid anterior pituitary...... 34 Dehydrogenase 2 deficiency...... 24 Antithrombin III deficiency...... 69 5- Fluorouracil (5FU)...... 66 aortic aneurysm...... 22 6-mercaptopurine...... 67 APC...... 31 6-thioguanine...... 67 APC resistance...... 70 Aarskog syndrome...... 12 APOA1...... 43 ABCC8...... 46, 50 APOB...... 44 abdominal pain...... 51, 52, 63, 64, 65, 66 APOE...... 44 abortion...... 75, 76 Apolipoprotein A1...... 43 absence of the radius...... 20 Apolipoprotein B...... 44, 83 ACADM...... 50 Apolipoprotein E...... 44, 83 ACE...... 69, 83 AR...... 62 Achondroplasia...... 68 arrhythmia...... 9, 10, 41 acroparesthesias...... 44 Arrhythmogenic right activated protein C resistance...... 70 ventricular Acute intermittent Porphyria...... 51 cardiomyopathy/dysplasia...... 9 ACVRL1...... 17 arterial tortuosity...... 22 ADLD...... 55 arteriovenous malformations...... 17 ADPKD...... 38 arthralgia...... 65, 66 Adult dominant polycystic arthralgias...... 65, 66 kidney disease...... 38 arthritis...... 41, 66 AFF2...... 15 Arthrochalasia...... 22 AKT1...... 18 arthropathy...... 64 ALDOB...... 63 ARVC/D...... 9 Alpha1-Antitrypsin Deficiency...... 43, 83 astrocytoma...... 35 Alport syndrome...... 39, 83 AT3D...... 69 Alzheimer disease...... 44 ataxia...... 14, 53, 54, 56, 83 amenorrhea...... 38 Ataxia teleangiectasia...... 31 Amsterdam Criteria...... 32 atherosclerosis...... 43, 45 amyloidosis...... 65, 66 ATM...... 31 anemia...... 28, 29, 53 ATP7B...... 42 Angelman syndrome...... 12 atrophic scarring...... 21 angiokeratomas...... 44 ATXN1...... 56 angiomyolipoma...... 36 ATXN2...... 57 Angiotensin converting enzyme..... 69, 83 ATXN3...... 57

84 Index

ATXN7...... 58 CACNA1A...... 57 autism...... 19, 36 CADASIL...... 55, 83 autoinflammation...... 66 café au lait spots...... 35 autonomic abnormalities...... 55 CAH...... 23, 38 Autosomal dominant cardiac failure...... 54 adult-onset demyelinating cardiac hypertrophy...... 17 leukodystrophy...... 55 cardiomyopathy...... 9, 53, 54, 60 axillary and inguinal freckling...... 35 Cardiomyopathy...... 10 azathioprine...... 67 carpal tunnel syndrome...... 60 AZF...... 27 cataplexy...... 37 azoospermia...... 27 cataract...... 61 Azoospermia factor...... 27 Catecholaminergic polymorphic balance dysfunction...... 35 ventricular tachycardia...... 10 Bannayan-Riley-Ruvalcaba CBAVD...... 27 syndrome...... 36 C-Cell carcinoma...... 34 Bechterew disease...... 37 Celiac disease...... 27, 37, 63, 83 Beckwith-Wiedemann centrocecal scotoma...... 25 syndrome...... 13, 73 CEQAS...... 84 behavioural abnormalities...... 82 cerebellar ataxia...... 31, 53, 57, 58 beta cell autoimmunity...... 47, 48, 49 Cerebral Autosomal Dominant Bethesda Guidelines...... 32 Arteriopathy with bifid uvula...... 22 Subcortical Infarcts and bilateral breast cancer...... 32 Leukoencephalopathy...... 55 bilateral neuropathy...... 26 cerebral seizures...... 82 blistering...... 52 CF...... 43 bloating...... 63 CFTR...... 27, 43, 64 blue sclera...... 23 Charcot-Marie-Tooth disease...... 58, 83 bone fragility...... 23 Charcot-Marie-Tooth disease type 1A.... 58 brachydactyly...... 12 Charcot-Marie-Tooth disease type 1B.... 59 BRAF...... 16, 17 Charcot-Marie-Tooth disease type 2A.... 59 BRCA1...... 32 Charcot-Marie-Tooth disease type X1.... 60 BRCA2...... 32 CHEK2...... 33 breast/ovarian cancer...... 32, 33 chorea...... 42, 53 bronchiectasis...... 43, 64 choreatic movements...... 56 Brugada syndrome...... 9 choreoathetosis...... 31, 42 BVDH...... 84 chorioamnionitis...... 26 BWS...... 13 chromosomal microarray....75, 76, 78, 82

85 Index

chromosomal rearrangement...... 80 aplasia of the vas deferens...... 27 Chromosome analysis congenital heart defect...... 17 from amniotic fluid...... 75 congenital heart disease...... 14 Chromosome analysis from peripheral congestive heart failure...... 41 lymphocytes...... 77 connective tissue nevi...... 18, 36 Chromosome analysis COPD...... 43 from products of conception...... 78 corneal arcus...... 45 chronic inflammatory disease...... 64 coronary artery disease...... 45, 69 Chronic neurologic cutaneous cortical blindness...... 54 and articular syndrome...... 64 Costello syndrome...... 13 chronic obstructive Cowden syndrome...... 36 pulmonary disease...... 43 CPEO...... 53 Chronic progressive CPVT...... 10 external ophthalmoplegia...... 53 craniosynostosis...... 22 chronic ulcerating lesions on skin...... 52 creatine phosphokinase...... 60 CINCA...... 64 Crigler-Najjar syndrome...... 40 CK...... 60 Crohn disease...... 28 cleft palate...... 14, 22 cryptorchidism...... 17 cloverleaf skull deformity...... 68 cryptozoospermia...... 27 CMT...... 58 CYP11B1...... 23 CMT1A...... 58, 59, 60 CYP17A1...... 24 CMT1B...... 59 CYP21A2...... 23 CMT2A...... 59 Cystic Fibrosis...... 43, 83 CMTX1...... 60 cystic kidney...... 15 CNBP...... 61 Cytogenetic External Quality coarse facies...... 13 Assessment Service...... 84 COL1A1...... 22, 23, 51 CytoSNP-850K...... 75, 76, 82 COL1A2...... 22, 23 daytime sleepiness...... 37 COL3A1...... 21 deafness...... 16 COL4A3...... 39 delayed motor milestones...... 18 COL4A4...... 39 dementia...... 54, 55, 56 COL4A5...... 39 demyelinating peripheral neuropathy.. 58 COL5A1...... 21 dentinogenesis imperfecta...... 23 COL5A2...... 21 Deutsche Gesellschaft für Congenital adrenal Abstammungsbegutachtung...... 83 hyperplasia...... 23, 38, 83 DGAB...... 83 Congenital bilateral DGS2...... 14

86 Index

Diabetes...... 47, 48, 49 extensor plantar responses...... 56 Diabetes-Deafness syndrome...... 54 F13A1...... 70 DiGeorge syndrome...... 14 F2...... 72 Disproportionate short stature...... 68 F5...... 26, 70, 72 disturbance of speech...... 56 F8...... 29 DMD...... 60 F9...... 30 DMD/BMD...... 60 Fabry disease...... 44, 83 DMPK...... 61 Faciogenital Dysplasia...... 12 Down syndrome...... 80 Factor II...... 72, 83 DPYD...... 66, 83 Factor V...... 26, 70, 83 DQA1...... 27 Factor XIII, A1 subunit...... 70 DQB1...... 27 failure to thrive...... 13, 50 dysarthria...... 56, 57, 58 Familial adenomatous polyposis.... 31, 83 dyslipoproteinemia...... 44 Familial cold autoinflammatory dysmorphic syndrome...... 77, 81 syndrome...... 65 dysphagia...... 57, 58 Familial hypercholesterolemia...... 45, 83 ear creases/pits...... 13 Familial mediterranean fever...... 65 early onset of tumors...... 34 FAP...... 31 ECG...... 9, 11, 16 fasciculations...... 62 ectopia lentis...... 22 Favism...... 29 Ehlers-Danlos syndrome type I+II...... 21 FBN1...... 22 Ehlers-Danlos syndrome type IV...... 21 FCAS...... 65 Ehlers-Danlos syndrome type VI...... 21 feeding difficulties...... 18 Ehlers-Danlos syndrome feeding difficulty...... 13 type VIIA+B...... 22 ferritin...... 40, 41 emphysema...... 43 fetal malformation...... 75 EMQN...... 83 FGB...... 70 end stage renal disease...... 39 FGD1...... 12 ENG...... 17 FGFR1...... 16 ependymomas...... 35 FGFR3...... 68, 83 epidermal nevi...... 18, 36 fibrinogen...... 70 European Molecular fifth-finger clinodactyly...... 19 Genetics Quality Network...... 83 FISH...... 7, 78, 79, 80, 81, 84 exanthema...... 66 fluorescence in excessive bleeding...... 29, 30 situ hybridization...... 78, 79 excessive eating...... 18 FMF...... 65 exocrine pancreas insufficiency..... 43, 64 FMR1...... 14

87 Index

Fragile X syndrome...... 14, 15 Glycoprotein IIIa...... 71, 83 FraX-A...... 14 gonadal dysgenesis...... 38 FraX-E...... 15 gonosomal chromosome changes...... 77 Friedreich Ataxia...... 56 growth anomalies...... 82 frontal bossing...... 68 growth retardation...... 82 Fructose intolerance...... 45, 63 gynecomastia...... 62 FXN...... 56 H19...... 13, 19 FXTAS...... 14 habitual miscarriages...... 26, 77, 81 G6PD...... 29 Habitual miscarriages...... 26 gait ataxia...... 12 hamartoma...... 36 gait disturbance...... 42 HAMP...... 40, 41 gait unsteadiness...... 57 HBA1...... 28 Gardner syndrome...... 31 HBA2...... 28 gastrointestinal bleeding...... 17 HBB...... 28, 29 GATA3...... 15 HBOC...... 32 Gaucher cells...... 45 HDR...... 15 Gaucher disease...... 45, 83 headache...... 55 GBA...... 45 hearing loss...... 15, 35, 54, 59 G-banded chromosome hemangioblastoma...... 37 analysis...... 75, 76, 77, 78 hematuria...... 15 GCK...... 46, 47, 48, 50 hemihypotrophy...... 19 genital ambiguity...... 23, 24 hemiparesis...... 54 genital hypoplasia...... 18 Hemochromatosis type 1...... 40 genital malformations...... 48 Hemochromatosis type 2A and 2B...... 41 gestational diabetes...... 47 Hemochromatosis type 3...... 41 Gilbert syndrome...... 42, 67, 83 Hemochromatosis type 4...... 41 GJB1...... 60 hemoglobin A2...... 28 GLA...... 44 Hemophilia A...... 29, 83 glomerular basement membrane...... 39 Hemophilia B...... 30 Glucose-6-Phosphate hemorrhage...... 29, 30 Dehydrogenase Deficiency.....29, 45, 83 hemorrhagic diathesis...... 30 glucosuria with no signs Hepato-, splenomegaly...... 42 of hyperglycemia...... 39 hepatoblastoma...... 13 glucosylceramide...... 45 hepatomegaly...... 50 GLUD1...... 46 hepatosplenomegaly...... 45 gluten-sensitive enteropathy...... 27 Hereditary Breast/Ovarian cancer...... 32 Glycoprotein Ia...... 71, 83 hereditary hemorrhagic

88 Index

telangiectasia...... 17 Hyperphenylalaninemia...... 51 Hereditary neuropathy, hyperpigmentation...... 52 with liability to pressure palsies...... 60 Hyperproinsulinemia...... 24, 46 Hereditary non-polyposis hypersomnia...... 37 colorectal cancer...... 32 hypertelorism...... 12, 17, 22, 82 Hereditary pancreatitis...... 64, 83 hypertension...... 20, 23, 24, 38, 69 HFE...... 40, 41 hypertrichosis...... 52 Hibernian fever...... 66 hypocalcemia...... 15 HIDS...... 65 Hypochondroplasia...... 68 hip dislocation...... 22 hypoglycemia...... 13, 46, 50, 63 hirsutism...... 23 hypogonadism...... 18, 61 HJV...... 40, 41 hypogonadotropic hypogonadism...... 16 HLA-B27...... 37 hypohidrosis...... 44 HMBS...... 51, 52 hypokalemia...... 23, 24 HNF1A...... 47, 48, 50 Hypoparathyroidism, HNF1B...... 47, 48, 50 Deafness, and Renal Disease...... 15 HNF4A...... 47, 48, 50 hyposmia...... 16 HNPCC...... 32, 83 hypothyroidism...... 20 HNPP...... 60 hypotonia...... 12, 18, 21, 46, 53, 62, 68 homocysteinemia...... 71 Ichthyosis...... 80 Homocysteinemia...... 71, 83 idiopatic short stature...... 69 homocystinuria...... 71 IgD levels...... 65 hormone substitution therapy...... 51 IGF2...... 19 HRAS...... 13 IHH...... 16 HSD3B2...... 24 immunodeficiency...... 31 HTT...... 56 impaired cortisol synthesis...... 24 Huntington disease...... 56, 83 Infertility...... 27 hyperandrogenemia...... 23 inflammation...... 65 Hyperbilirubinemia...... 40, 42, 67 Inflammatory bowel disease...... 28 hypercholesterolemia...... 44 INS...... 46, 49, 50 Hypercholesterolemia...... 45 insulin resistance...... 46 hyperextensible skin...... 21 intention tremor...... 57 Hyperglycemia...... 50 intestinal inflammation...... 28 Hyper-IgD syndrome...... 65 intrauterine growth retardation...... 19, 50 Hyperinsulinism...... 24, 46 involuntary childlessness...... 77, 78 hyperkinesia...... 56 Irinotecan...... 67 hyperparathyroidism...... 34 iron overload...... 41

89 Index

ITGA2...... 71 lentiginosis...... 16 ITGB3...... 71 LEOPARD syndrome...... 16 jaundice...... 40, 42 LEP...... 25 joint hypermobility...... 21, 22 LEPR...... 25 joint laxity...... 21, 22, 62 Leri-Weill syndrome...... 69 KAL1...... 16 lethargy...... 50 Kallmann syndrome...... 16, 24, 80 leukemia...... 31, 34 Kayser-Fleischer ring...... 42 LHON...... 25, 53 KCNE1...... 11 Li-Fraumeni syndrome...... 34 KCNE2...... 11 light-sensitive dermatitis...... 52 KCNH2...... 11 Lisch nodules...... 35 KCNJ11...... 46, 50 liver fibrosis...... 40, 41 KCNQ1...... 11 LMNA...... 10 KCNQ1OT1...... 13 LMNB1...... 55 Kearns-Sayre syndrome...... 53 lobeless ears...... 21 Kennedy disease...... 62 Loeys-Dietz syndrome...... 22 kernicterus...... 40, 42 LOH...... 82 Kinship analyses...... 83 long extremities...... 22 KLF11...... 49 Long QT syndrome...... 11 KRAS...... 17 loss of heterozygosity...... 82 KSS...... 53 low birth weight...... 50 Kugelberg-Welander disease...... 62 low C-peptide levels...... 50 Kyphoscoliosis...... 21 LQT1...... 11 lactic acidosis...... 53 LQT2...... 11 Lactose intolerance...... 47, 63, 83 LQT3...... 11 lactose-containing food...... 63 LQT5...... 11 Langer mesomelic dysplasia...... 69 LQT6...... 11 LCT...... 63, 83 lumbar lordosis...... 68 LDLR...... 45 Machado-Joseph disease...... 57 LDLRAP1...... 45 macrocephaly...... 20, 68, 82 learning disability...... 20 macroglossia...... 13 Leber hereditary optic neuropathy...... 53 macrosomia...... 13 Leber’s hereditary optic neuropathy... 25, maculopapular rash...... 65 83 Major Histocompatibility Complex. 27, 37 Leiden mutation...... 26, 70 Male infertility...... 27 Leigh- / Neuropathy, Mannose binding lectin...... 26 ataxia, retinitis pigmentosa...... 53 Marfan syndrome...... 22, 83

90 Index

Martin-Bell syndrome...... 14 MJD...... 57 maternal age...... 75, 76, 79 MLH1...... 32 Maturity-Onset Diabetes MODY...... 24, 47, 83 of the Young...... 24, 47 MODY1...... 47 MBL...... 26 MODY10...... 49 MBL2...... 26 MODY2...... 47 MC3R...... 25 MODY3...... 48 MC4R...... 25 MODY4...... 48 MCAD Deficiency...... 50 MODY5...... 48 meconium ileus...... 43, 64 MODY6...... 49 MECP2...... 19 MODY7...... 49 Medium-Chain Acyl-CoA monozygotic/dizygotic twins...... 74 Dehydrogenase...... 50 MPZ...... 59 medullary carcinoma of the thyroid..... 34 MSH2...... 32 MEFV...... 65 MSH6...... 32 MELAS...... 54 MT-ATP6...... 53 MEN1...... 34 MTC...... 34 MEN2...... 34 MTHFR...... 71, 83 meningiomas...... 35 MTND1...... 25 mental retardation...... MTND4...... 25 ...... 12, 14, 15, 17, 19, 20, 81 MTND6...... 25 Mental retardation...... 82 MT-TK...... 54 MERRF...... 54 MT-TL1...... 54 metabolic alkalosis...... 24 Muckle-Wells syndrome...... 66 MFN2...... 59 Multiple endocrine neoplasia type I..... 34 micro- or macrohematuria...... 39 Multiple endocrine neoplasia type II.... 34 microcephaly...... 12 muscle weakness...... 56, 58, 61, 62 microdeletion syndrome...... 80 muscular dystrophy...... 61, 83 micromelia...... 68 Muscular dystrophy microsatellite...... 73, 74, 78 type Duchenne/Becker...... 60 migraine...... 55 MUTYH...... 31 Miller-Dieker syndrome...... 80 MVK...... 65 mitochondrial disease...... 53 myalgia...... 66 mitochondrial genome...... 25, 53, 54 myalgias...... 65 Mitochondrial myopathy, MYBPC3...... 10 encephalopathy, lactic acidosis, MYH7...... 10 and stroke-like episodes...... 54 myocard infarct...... 43

91 Index

Myoclonic epilepsy associated Olaparib...... 32 with ragged-red fibers...... 54 oligozoospermia...... 27 myoclonus epilepsy...... 54 omphalocele...... 13 myofiber degeneration...... 60 OPA1...... 26 myopathy...... 54, 61, 67 ophthalmoparesis...... 57 myotonia...... 61 ophthalmoplegia...... 53 Myotonic dystrophy type 1...... 61 optic atrophy...... 54 Myotonic dystrophy type 2...... 61 Optic Atrophy 1...... 26 Narcolepsia...... 37 or FraX-associated tremor/ataxia NARP syndrome...... 53 syndrome...... 14 nausea...... 63, 64 Osler-Rendu-Weber disease...... 17 Neonatal Diabetes...... 24, 50 Osteogenesis Imperfecta...... 23, 83 neonatal onset multisystemic Osteoporosis...... 51, 83 inflammatory disease...... 64 osteosarcomas...... 34 nephrotic syndrome...... 15 overgrowth...... 18, 20, 22, 36 neural tube defects...... 75 overgrowth of body parts...... 18 neuroblastoma...... 13 PAH...... 51 NEUROD1...... 49 PAI1...... 72, 83 neurofibromas...... 35 PALB2...... 33 Neurofibromatosis type 1...... 35, 83 pancreatic abnormalities...... 48 Neurofibromatosis type 2...... 35 pancytopenia...... 45 neurologic disturbances...... 51 parkinsonism...... 57 NF1...... 35 PCSK9...... 45 NF2...... 35 PDX1...... 48 NLRP3...... 64, 65, 66 Pearson syndrome...... 53 NOD2...... 28, 83 peritonitis...... 65 NOMID...... 64 peroneal palsy...... 60 Noonan syndrome...... 17 pes cavus...... 58 nosebleeding...... 17 Phenylketonuria...... 51, 83 NOTCH3...... 55 pheochromocytoma...... 34, 37 NSD1...... 20 photosensitivity...... 52 nystagmus...... 57 pigmentary retinopathy...... 53 obesity...... 18, 25 pinched nose...... 21 Obesity...... 25, 50 PKD1...... 38 obstructive lung disease...... 43, 64 PKD2...... 38 ocular hypertelorism...... 16 PKP2...... 9 oculomotor apraxia...... 31 PKU...... 51

92 Index

Plasminogen-Activator-Inhibitor PTEN...... 36 type 1...... 72, 83 PTEN hamartoma tumor syndrome..... 36 pleuritis...... 65 PTPN11...... 16, 17 PLOD1...... 21 pulmonary stenosis...... 16, 17, 20 PMP22...... 58, 60 PWS...... 18, 73 polyploidy...... 78 RAD51C...... 33 POMC...... 25 RAF1...... 16, 17 poor feeding...... 46 Rapid prenatal diagnostics...... 79 Porphyria...... 51 RBM8A...... 20 Porphyria Cutanea tarda...... 52 RCAD...... 48 porphyrinogenic drugs...... 51 recurrent preterm births...... 26 Prader-Willi syndrome...... 18 redundant skin...... 13 precocious puberty...... 23 Reference Institute for Bioanalytics..... 83 Prenatal chromosome diagnostics...... 75 regression...... 19, 53 pressure neuropathies...... 60 renal and liver cysts...... 38 PROC...... 72 renal cell carcinoma...... 37 PROCR...... 72 Renal Cysts and Diabetes syndrome.... 48 progressive scoliosis...... 21 renal disease...... 15, 44, 48 proinsulin...... 46 Renal glucosuria...... 39, 52 PROK2...... 16 renin...... 23, 24 PROKR2...... 16 repetitive, stereotypic PROMM...... 61 hand movements...... 19 Protein C deficiency...... 72 RET...... 34 Protein C receptor...... 72 retinal angioma...... 37 Protein Z deficiency...... 73 retinal dystrophy...... 58 proteinuria...... 15, 39, 44 Rett syndrome...... 19 Proteus syndrome...... 18, 36 RfB...... 83 Proteus-like syndrome...... 36 rhabdomyosarcoma...... 13 Prothrombin...... 72, 83 rigid dystonia...... 42 proximal muscular dystrophy...... 60 rupture of inner organs...... 21 PROZ...... 73 RYR2...... 10 PRSS1...... 64 saccadic eye movements...... 57 pseudobulbar involvement...... 42 salt wasting...... 23, 24 pseudohypertrophy...... 60 SBMA...... 62 psoriatic arthritis...... 37 SCA1...... 56 psychological distress...... 75, 76, 79 SCA2...... 57 psychomotor delay...... 62 SCA3...... 57

93 Index

SCA6...... 57 SPINK1...... 64 SCA7...... 58 Spinocerebellar ataxia type 1...... 56 scars...... 21, 22 Spinocerebellar ataxia type 2...... 57 scleral fragility...... 21 Spinocerebellar ataxia type 3...... 57 SCN5A...... 9, 11 Spinocerebellar ataxia type 6...... 57 scotoma...... 26 Spinocerebellar ataxia type 7...... 58 seizures...... 12 Spinocerebellar ataxias...... 56, 83 sensorineural hearing loss...... 39 spondyloarthropathy...... 37 serositis...... 65 SQT1...... 11 SERPINA1...... 43, 83 SQT2...... 11 SERPINC1...... 69 SRS...... 19, 69, 83 SERPINE1...... 72 SRY...... 38 severe pain in the extremities...... 44 ß-Fibrinogen...... 70, 83 shawl scrotum...... 12 Statin-induced myopathy...... 67 Short QT syndrome...... 11 statins...... 67 short stature...... 12, 13 Steinert disease...... 61 SHOX...... 69, 80, 83 sterility...... 77 SHOX deficiency...... 69, 83 Steroid 11-beta-Hydroxylase sickle cell...... 29 deficiency...... 23 Sickle Cell Anemia...... 29 stillbirth...... 75, 76 Silver-Russell syndrome...... 19, 69, 73 STR...... 74 skin fragility...... 52 stroke-like episodes...... 54 skin hyperextensibility...... 21, 22 subcortical infarcts...... 55 SLC40A1...... 40, 41 subluxations...... 22 SLC5A2...... 39 Subtelomere analysis...... 81 SLCOB1...... 67 sudden cardiac death...... 9, 10, 11 slow nerve conduction velocity...... 58 sweat chloride concentration...... 43, 64 Smith-Magenis syndrome...... 80 swelling of the extremities...... 65 SMN1...... 62 symmetric demyelination...... 55 SNRPN...... 12, 18 syncope...... 10 soft tissue sarcomas...... 34 synovitis...... 65 SOS1...... 17 tachycardia...... 10 Sotos syndrome...... 20 TAR...... 20 spasticity...... 53, 57 tendinous xanthomas...... 45 speech impairment...... 12 testicular atrophy...... 62 Spinal and Bulbar Muscular Atrophy... 62 testicular feminization...... 38 Spinal muscular atrophy type...... 62 tetany...... 15

94 Index tetralogy of Fallot...... 14 UGT1A1...... 40, 42, 67 TFR2...... 40, 41 ultrasound...... 75, 76, 77, 79 TGFBR1...... 22 UPD11...... 13, 73 TGFBR2...... 22 UPD14 608149...... 73 Thanatophoric dysplasia...... 68 UPD15...... 12, 18, 73 THBD...... 73 UPD6...... 50, 73 Thiopurin S-Methyltransferase UPD7...... 19, 73 Deficiency...... 67, 83 UROD...... 52 thrombocytopenia...... 20 urticaria...... 65 Thrombocytopenia-absent Variegate Porphyria...... 52 radius syndrome...... 20 vascular malformations...... 18 thromboembolic disease...... 69, 71 VDR...... 51 Thrombomodulin defect...... 73 venous thromboembolism...... 72, 73 thrombophilia...... 69, 70, 72, 73 ventricular fibrillation...... 11 thrombosis...... 26, 70 ventricular septal defect...... 14 tinnitus...... 35 vesicoureteral reflux...... 15 tissue fragility...... 21 vestibular schwannoma...... 35 TNFRSF1A...... 66 VHL...... 37 TNNI3...... 10 vibratory sense...... 56 TNNT2...... 10 virilization...... 23 tonic-clonic seizures...... 54 visceromegaly...... 13 TP53...... 34 visual failure...... 25 TPMT...... 67, 83 Von-Hippel-Lindau syndrome...... 37, 83 transferrin...... 40, 41 Von-Willebrand disease...... 30 translocation...... 80 VWF...... 30 TRAPS...... 66 WBSCR...... 20 tremor...... 14, 42, 59 Werdnig-Hoffmann disease...... 62 triangular shaped face...... 17 white matter lesions...... 55 truncus arteriosus...... 14 Williams-Beuren syndrome...... 20, 80 TSC1...... 36 Wilms tumor...... 13 TSC2...... 36 Wilson disease...... 42, 83 Tuberous sclerosis...... 36 Wolff-Parkinson-White syndrome...... 54 Tumor necrosis factor receptor- XX-males...... 38 associated periodic syndrome...... 66 α-Galactosidase-A deficiency...... 44 tumors of parathyroids...... 34 α-Thalassemia...... 28 Turcot syndrome...... 31 β–Thalassemia...... 28 UBE3A...... 12 95 Ärztliche Leitung: Dr. med. Dr. rer. nat. Claudia Nevinny-Stickel-Hinzpeter Fachärztin für Humangenetik

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